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The Oncologist, Vol. 13, No. 4, 361-369, April 2008; doi:10.1634/theoncologist.2007-0207
© 2008 AlphaMed Press

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Breast Cancer

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

Alexandros Ardavanisa, Panteleimon Kountourakisa, Flora Kyriakoub, Savoula Mallioua, Ioannis Mantzarisa, Anastasia Garoufalib, Ioulia Yiotisb, Andreas Scorilasc, Nikolaos Baziotisb, Gerasimos Rigatosa

aFirst Department of Medical Oncology and bNuclear Medicine Department, Saint Savas Oncology Hospital, Athens, Greece; cBiology Department, University of Athens, Athens, Greece

Key Words. HER-2/neu • HER-2 ECD • Metastatic breast cancer • Anthracycline/taxane resistant • Salvage

Correspondence: Alexandros Ardavanis, M.D., Saint Savas Oncology Hospital, 171 Alexandras Avenue, 115 22 Athens, Hellas. Telephone: 30-694-4421525 (mobile); Fax: 30-210-6409508; e-mail: ardavanis{at}yahoo.com

Received December 26, 2007; accepted for publication March 7, 2008.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 IHC and CISH
 Results
 Discussion
 Author Contributions
 References
 
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.


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 IHC and CISH
 Results
 Discussion
 Author Contributions
 References
 
The human epidermal growth factor receptor 2 (HER-2, neu, ErbB-2, p185HER-2) is a transmembrane glycoprotein consisting of an extracellular domain (ECD) and an intracellular tyrosine kinase domain [1, 2]. The HER-2/neu proto-oncogene mediates both proliferation and differentiation in normal epithelial cells. It is, however, amplified and/or overexpressed in approximately 25%–30% of invasive breast cancers [3, 4]. As a result of gene amplification, breast cancers exhibit a more aggressive biological behavior, including poorer response rates to alkylating agent–based chemotherapy and endocrine therapy, resulting in shorter progression-free and overall survival times [3,5].

The ECD of the protein (p105) is frequently cleaved from the surface of HER-2/neu–expressing cells and released into the circulation, where it is detectable by enzyme-linked immunosorbent assay (ELISA) in as many as 45% of patients with metastatic disease [6] and approximately 15%–30% of presurgical breast cancer patients at the time of diagnosis [7]. Testing for serum HER-2 ECD level is not affected by other members of the ErbB family, nor by treatment with trastuzumab, the anti-HER-2 monoclonal antibody, because the ELISA system recognizes different epitopes [8].

In HER-2–positive disease, increasing levels of serum HER-2 ECD have been associated with progressive metastatic disease and poor responses to chemotherapy and hormonal therapy [9]. Similarly, in patients treated with trastuzumab, response rates are higher in patients with elevated (≥15 ng/ml) HER-2 ECD at baseline, and an early decrease in levels predicts response and progression-free survival [10]. Bearing this in mind, the soluble isoforms of HER-2 are being examined as potential biomarkers for the detection of early recurrence or metastasis and for predicting response to therapy [11, 12]. Furthermore, there is evidence that correlates the serum HER-2 ECD level with tumor HER-2 status detected by immunohistochemistry (IHC) [13].

HER-2 status is typically determined by IHC with supplementation by fluorescence or chromogenic in situ hybridization (FISH/CISH) for intermediate scores of 2+. Patients deemed to be 3+ by IHC or FISH/CISH positive (gene amplified) are considered eligible for treatment regimens containing trastuzumab. However, there are some patients that express significant levels of HER-2 protein but are not scored as positive; similarly, there are incidents of patients that have been found to have HER-2–amplified metastatic disease but nonamplified/overexpressing primary lesions [14].

Therefore, the true HER-2 status of some tumors may be underestimated, resulting in inappropriate prognostic evaluation, inadequate treatment, and unexpected early relapse. We have thus questioned the utility of the serum HER-2 ECD level as a surrogate marker for HER-2–positive disease, because these levels do correlate with relapse and outcome. In light of this, we have initiated a feasibility study to investigate the efficacy of trastuzumab treatment in what are traditionally HER-2–negative women but with above normal levels (≥15 ng/ml) of serum HER-2 ECD at the time of disease progression, following failure of at least two prior chemotherapeutic regimens containing an anthracycline and a taxane.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
IHC and CISH
 Results
 Discussion
 Author Contributions
 References
 
Patient Population
Serum was obtained from 95 consecutive advanced breast cancer patients meeting the study entry criteria. The study was reviewed and approved by the institutional review board. Signed written informed consent was obtained from all patients prior to study entry, and the study was conducted according to European guidelines for good clinical practice. Patients eligible for participation were women with metastatic breast cancer who had progressed after at least two lines of chemotherapy, including an anthracycline and a taxane. All patients were HER-2 negative according to IHC, and trastuzumab naive. Diagnoses were performed in various centers and laboratories, and therefore tumor blocks from all patients were centrally tested for HER-2 expression by IHC prior to study entry.

All previous patient data were extracted from their files including the tumor–node–metastasis clinical/pathological stage at initial diagnosis, previous treatment regimens, outcomes, and toxicity. All patients were given a full clinical examination to determine their extent of disease prior to study entry. A full cardiologic evaluation was performed on all patients, including a routine electrocardiogram and echocardiographic study of left ventricular ejection fraction or equilibrium radionuclide ventriculography.


   IHC AND CISH
Top
 Abstract
 Introduction
 Patients and Methods
 IHC and CISH
Results
 Discussion
 Author Contributions
 References
 
The IHC analysis was performed on serial 3-µm thick sections from original blocks placed on SuperFrost® Plus slides (Menzel, Braunschweig, Germany). HER-2 antibodies included HercepTestTM (rabbit anti-human HER-2/neu polyclonal antibody; Dako Corporation, Carpinteria, CA) and CB11 (mouse anti-human monoclonal antibody; Ventana Medical System Inc., Tuscon, AZ) for the evaluation of protein expression. The intensity of the membrane staining was evaluated according to Dako HercepTestTM criteria: score 0, no or up to 10% membrane staining; score 1+, partial and/or faint membrane staining present in >10% of tumor cells; score 2+, weak to moderate complete membrane staining present in >10% of tumor cells; and score 3+, strong, complete membrane staining present in >10% of tumor cells. By Dako HercepTestTM and CB11 criteria, scores of 0 or 1+ were considered as negative, a score of 3+ was indicative of overexpression, while tumors with a 2+ score were further analyzed by CISH. Sections for CISH (4-µm thick) were placed on capillary gap slides (Dako Cytomation). A commercially available probe for the HER-2 gene was used according to the manufacturer's instructions. Zymed's SPoT-Light® CISH (Invitrogen Corporation, Carlsbad, CA) was used for CISH detection. Note that analysis of patients' tumor blocks by CISH was performed retrospectively and was not used as a standard entry criterion.

Sample Collection and Serum HER-2/neu Antigen Testing
The first (baseline) serum sample for each patient was taken before trastuzumab-based therapy was started. Patients were subsequently monitored every 3 months during trastuzumab-based therapy, with at least two subsequent serial serum samples being collected at least 9 weeks apart at the discretion of the treating physician. Serum samples were processed immediately upon collection of blood and stored at –80°C. Frozen samples were treated immediately upon initial thawing.

Serum HER-2 ECD levels were determined using the Bayer Immuno-1 assay (Bayer Corporation, Tarrytown, NY). This assay is currently approved by the U.S. Food and Drug Administration with an indication for follow-up and monitoring of patients with metastatic breast cancer. This assay is based on two monoclonal antibodies directed against the ECD of the HER-2 antigen. It is considered accurate, precise, and resistant to interference. A serum HER-2/neu concentration of 15 ng/ml has been defined as the upper limit of normal, and the assay is reliable for longitudinal monitoring [15].

Evaluation of Tumor Response
Standard World Health Organization criteria were used for response [16, 17]: complete response (CR), no clinically detectable cancer is found after treatment; partial response (PR), a ≥50% decrease in measurable tumor mass is seen, no new areas of tumor develop, and no area of tumor shows progression; minimal response (MR), the same as partial response but the response is <50%; progressive disease (PD), the mass of one or more tumor sites increases >25% or new lesions appear; and stable disease (SD), a measurable mass does not meet the criteria for CR, PR, MR, or PD. Clinical benefit equals the sum of the objective responses and SD events lasting >6 months.

Treatment
Patients were treated with one of the following regimens, at the physician's decision. Trastuzumab was administered on the first cycle at a loading dose of 8 mg/kg. Subsequent administrations were at 6 mg/kg, every 3 weeks. Chemotherapy consisted of either 75 mg/m2 of docetaxel every 3 weeks (administered on the same day, following trastuzumab) or 90 mg/m2 of paclitaxel administered weekly. This combination was repeated for a maximum of six cycles. Standard premedication and antiemetic prophylaxis were used.

Trastuzumab was continued at 6 mg/kg every 3 weeks in all patients exhibiting a response (biochemical and/or clinical) until disease progression, at the discretion of the treating physician. In all patients with skeletal metastasis, palliative oral or i.v. bisphosphonates were either initiated or continued.

Statistics
Continuous data were summarized using descriptive statistics. For the variables of interest, the mean value ± standard deviation was assessed. A Student's t-test was used for the statistical study of the parity of two mean values, while a nonparametric Mann-Whitney test was used for mean values derived either from samples that did not follow a normal distribution or from small samples, and for patient demographics in relation to side effects. Analysis of variance for repeated measurements was used for the comparison of the mean values of different parameters for the different sampling times. Following the multiple comparison test, a Student's t-test for independent or related samples with a corrected level of significance according to the Bonferroni correction was performed. A p-value of .05 or less was considered to indicate statistical significance. Statistical analyses were performed using the computational package SPSS 10.0 (SPSS Inc., Chicago, IL). All patients were analyzed for safety.


   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 IHC and CISH
 Results
Discussion
 Author Contributions
 References
 
In total, 95 consecutive HER-2–negative, trastuzumab-naive breast cancer patients who had failed at least two prior chemotherapy regimens, including both taxane- and anthracycline-based regimens, were screened for study entry. Patient demographics and previous treatment data are shown in Table 1. Patients were considered eligible for salvage trastuzumab plus chemotherapy if they were found to be positive (>15 ng/ml) for elevated HER-2 ECD. In total, 22 breast cancer patients aged 32–73 years (median, 56 years) were identified as HER-2 ECD positive and received combined trastuzumab and taxane chemotherapy as a salvage treatment (Table 2). Three patients had a baseline HER-2 ECD level of 16–49 ng/ml and 18 patients had baseline HER-2 ECD levels of ≥50 ng/ml. Fifteen patients received trastuzumab plus docetaxel (75 mg/m2) every 3 weeks; 12 of these had previously been exposed to docetaxel, with a median docetaxel-free interval 9 months (range, 3–12), while three patients were previously exposed to paclitaxel, with a median paclitaxel-free interval of 6 months (range, 4–10). Seven patients were treated with 90 mg/m2 of paclitaxel weekly plus trastuzumab every 3 weeks; all these patients had previously been treated with paclitaxel, with a median paclitaxel-free interval of 8 months (range, 4–11).


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  		Table 1. Patient demographics—pretreatment data (adjuvant setting, first-line, second-line therapy)

 


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  		Table 2. Patient characteristics, HER-2 ECD levels, and event outcomes

 
In total, 72 (mean, 4.8 cycles per patient) trastuzumab plus docetaxel and 38 (mean, 5.2 cycles per patient) trastuzumab plus paclitaxel cycles were administered. Eighty-eight (mean, 4 cycles per patient) cycles of maintenance trastuzumab were administered.

Despite the advanced disease stage in these heavily pretreated patients, dose-limiting hematologic toxicities were, in general, moderate, with only three cases of febrile neutropenia in the trastuzumab plus docetaxel and one case of febrile neutropenia in the trastuzumab plus paclitaxel treated groups, respectively (Table 3).


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  		Table 3. Adverse events

 
The incidences of nonhematologic toxicity were moderate; severe neurosensory toxicity was reported in one patient in each treatment group. There were no treatment-related deaths.

Efficacy
Five patients obtained MRs (23%) and another 11 achieved SD (50%), giving a clinical benefit rate of 73% (Table 2). In two of the patients with SD, subjective improvement was noted (pain control and performance status improvement). The same was true in four of the six patients with PD despite objective deterioration.

Clinical and Biochemical Response
From the 22 treated patients, 96 serum samples were available for analysis (median, 4.3 per patient). The mean HER-2 ECD concentration at baseline was 122.82 ng/ml (18.5–250 ng/ml). During the course of trastuzumab-based treatment, this decreased to 54.25 ng/ml (range, 16.3–217 ng/ml), 34.34 ng/ml (range, 6.3–92 ng/ml), and 36.25 ng/ml (range, 7.1–91 ng/ml) at the three subsequent measurements of roughly 9-week intervals, respectively.

A decrease in HER-2 ECD was observed in responders (4 of 5 patients) and patients obtaining SD (7 of 11 patients) (Fig. 1). Two of the patients with PD also had similar declines. In five of the eight patients remaining alive and progression free after 12 months, HER-2 ECD levels remained within the normal range (not reported). In total, 18 patients demonstrated a biochemical response, six with normalization of levels after six courses of therapy (3 of 5 with MRs and 2 of 11 with SD); five of these remained alive for >12 months.


Figure 1
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  		Figure 1. Human epidermal growth factor receptor 2 extracellular domain (HER-2 ECD) levels over time.

 
Time to Progression and Overall Survival
The median time to progression (TTP) was 5 months (95% confidence interval [CI], 1.32–8.68 months) (Fig. 2A). In patients with a minor clinical response and/or biochemical response or SD, the TTP appeared to be slightly longer, with a median of 6.5 months. The median overall survival (OS) time was 12 months (95% CI, 9.085–14.915 months) (Fig. 2B).


Figure 2
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  		Figure 2. Time to progression (A) and overall survival time (B).

 
Nine patients (three with 2–3 years with liver metastasis) were clinically/biochemically progression free at 12 months. Fifteen patients (68.2%) were dead, including all patients with PD.

When patients with HER-2 gene amplification were removed from the dataset following retrospective analysis, no statistically significant differences were observed in event outcomes (data not shown). All three of these patients had biochemical responses, maintained SD, and received maintenance trastuzumab (Table 2).


   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 IHC and CISH
 Results
 Discussion
Author Contributions
 References
 
HER-2 status is both a prognostic and predictive factor for patients with breast cancer. The amplification of the gene for HER-2 or overexpression of the HER-2 protein as detected by IHC in the tumor has been linked to a poor prognosis and lesser response to a variety of systemic treatments [3, 18, 19]. With the incorporation of the anti-HER monoclonal antibody trastuzumab into chemotherapy regimens for both metastatic and, more recently, adjuvant HER-2–positive disease, there is an overwhelming need for markers of progression, allowing for monitoring of disease.

The distribution of cell populations within the tumor is heterogeneous and the optimum possible sampling of the pathologist may fail to detect one or more small populations. Moreover, fixing techniques may affect the reliability of the very sensitive IHC methods. Based on this, we hypothesized that cells with higher metastatic potential, such as those with HER-2 amplification, may migrate early in the course of tumor growth but at the same time remain "absent" or below the detectable "range" when primary cancer is excised.

The observation of HER-2–positive tumor cells in blood vessels in the absence of HER-2 positivity within the tumor supports our hypothesis [20]. Some clones with HER-2 amplification might escape detection by the best available methods or have already migrated when the tumor is excised. These clones eventually establish themselves and appear invisible by standard imaging techniques; however, these metastatic sites may be suspected if HER-2 ECD levels are measured before surgical excision of the primary tumor. Serum levels of HER-2 ECD have, for many years now, been used as a means of monitoring patient response and progression in the metastatic setting [10]. Because it is shed into the serum, this marker offers a clinically important tool for patient monitoring and possible patient selection not only for treatment with trastuzumab but also for the rapidly expanding series of newer anti-HER-2 agents, such as lapatinib. Apart from this marker being used for monitoring patient progression and response, there is a potential for the identification of patients that may benefit from HER-2 suppression without having strong HER-2–positive tumor expression. Patients that may be included in this group are those that are HER-2 negative in the primary tumor but incidentally HER-2 positive in metastatic lesions [14], and those that have no obvious metastatic disease by conventional screening methods yet have levels of HER-2 ECD above the 15 ng/ml threshold.

Recently the National Surgical Adjuvant Breast and Bowel Project (NSABP B-31 trial) reported that, when central testing of HER-2 status is used, benefit from adjuvant trastuzumab may not be confined to patients with IHC 3+ and/or FISH-positive tumors [21]. Evidence exists that, among patients with HER-2–positive tumors, there is a subset with elevated HER-2 ECD levels at baseline who, if they have normalization early in their treatment course, consequently display superior responses to those in patients that have persistently high levels [22]. Such a rapid correlation from a serum tumor marker would be extremely useful if the correlation held in larger studies. Some studies also suggest the utility of selecting patients solely on HER-2 ECD levels for subsequent treatment with trastuzumab-based therapy. Esteva et al. [12] reported that serum HER-2 concentrations decreased in 87% of responding patients, showing that changes in serum HER-2 ECD levels correlated with disease course. In addition, they showed that patients with baseline HER-2 ECD levels ≥15 ng/ml had an objective response rate (ORR) of 76%, compared with 33% for those with <15 ng/ml. Dnistrian et al. [23] reported an 83% ORR in those patients with baseline HER-2 ECD levels ≥15 ng/ml. However, in at least one study of HER-2 ECD kinetics in HER-2–positive breast cancer patients, the levels of the latter were positively correlated with the response rate but not with the progression-free and OS times [10]. These discrepancies in different studies could be attributed to the use of different techniques, differences in measuring protein expression, and the use of different cutoff levels to define a positive test. Although these studies were conducted in populations that were traditionally HER-2 positive (tumor positive for amplification and/or protein overexpression by IHC), they do indicate that the baseline level of serum HER-2 ECD may have potential as a predictive marker of response to anti-HER-2–based treatments.

Our data support this hypothesis, because in this population of heavily pretreated metastatic breast cancer patients, anti-HER-2 agents would not be considered to be effective. However, five of 22 patients with MRs and six patients with SD for ≥12 months were observed in our study. A biochemical response (at least a halving of the baseline level) was observed in 13 patients, indicating that there may be some distinct biological activity against the target by trastuzumab. Furthermore, six patients obtained a normalization of their HER-2 ECD levels within six courses of treatment.

TTP and OS times with third-line chemotherapy are usually only of a few months' duration; in our patients, the above variables seemed to be higher despite the fact that all patients were previously exposed to a regimen including a taxane. It is known that docetaxel and paclitaxel regimens produce objective responses and SD in HER-2–negative patients [24, 25]. In our patients, paclitaxel was administered weekly, a regimen eventually found to be superior in efficacy to the 3-weekly schedules; the Cancer and Leukemia Group B CALGB-9840 trial found that weekly administration of paclitaxel was superior to the standard 3-week regimen [26]. It should again be noted that, in our patients, taxane "refractoriness" was very probably present given the lack of any response to the previous administration of taxanes in the majority of patients (43% and 9% with PD and SD, respectively), while the median docetaxel- and paclitaxel-free intervals were short (9 and 8 months, respectively).

The incorporation of anti-HER-2 agents into the metastatic setting based on HER-2 ECD level could easily be implemented into routine practice because the determination of ECD levels by ELISA is widely available. The additional benefit of noninvasive monitoring of disease over time, as is commonly used with other tumor-associated markers (carcinoembryonic antigen, cancer antigen 15.3, etc.), would also prove to be extremely useful once prospective data correlate levels with disease (bulk/extent and/or outcomes).

Moreover, given the convenience of its determination, HER-2 ECD presumably offers the advantage of a "real-time biomarker," allowing the assessment of HER-2–positive load at any time in the course of breast cancer, as opposed to the "photographic" nature of the IHC and FISH/CISH techniques, which are limited to a single documentation. The true HER-2 status of some tumors might be underestimated, resulting in inappropriate prognostic evaluation, and thus inadequate treatment in the adjuvant setting or at "unexpected" early relapse.

To our knowledge, this is the first study assessing anti-HER-2–based treatment in HER-2–negative advanced breast cancer according to HER-2 ECD positivity. Other investigators are working in the same direction; hopefully, if our results are confirmed, a reliable tool for assessing and treating "hidden" HER-2–positive breast cancer will be added to our armamentarium.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Introduction
 Patients and Methods
 IHC and CISH
 Results
 Discussion
 Author Contributions
References
 
Administrative support: Alexandros Ardavanis, Nikolaos Baziotis, Gerasimos Rigatos

Conception/design: Alexandros Ardavanis

Provision of study materials or patients: Alexandros Ardavanis, Panteleimon Kountourakis

Collection/assembly of data: Alexandros Ardavanis, Panteleimon Kountourakis, Flora Kyriakou, Savoula Malliou, Ioannis Mantzaris, Anastasia Garoufali, Ioulia Yiotis, Andreas Scorilas

Data analysis and interpretation: Alexandros Ardavanis, Panteleimon Kountourakis

Manuscript writing: Alexandros Ardavanis, Panteleimon Kountourakis

Final approval of manuscript: Alexandros Ardavanis, Panteleimon Kountourakis, Flora Kyriakou, Savoula Malliou, Ioannis Mantzaris, Anastasia Garoufali, Ioulia Yiotis, Andreas Scorilas, Nikolaos Baziotis, Gerasi mos Rigatos


   REFERENCES
Top
 Abstract
 Introduction
 Patients and Methods
 IHC and CISH
 Results
 Discussion
 Author Contributions
 References
 

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F. J. Esteva
Commentary: Can Circulating HER-2 Extracellular Domain Predict Response to Trastuzumab in HER-2-Negative Breast Cancer?
Oncologist, April 1, 2008; 13(4): 370 - 372.
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