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Clinical Chemistry 48: 1314-1320, 2002;
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(Clinical Chemistry. 2002;48:1314-1320.)
© 2002 American Association for Clinical Chemistry, Inc.

Relationship of Serum HER-2/neu and Serum CA 15-3 in Patients with Metastatic Breast Cancer

Suhail M. Ali1,2, Kim Leitzel1, Vernon M. Chinchilli1, Linda Engle1, Laurence Demers1, Harold A. Harvey1, Walter Carney3, Jeffrey W. Allard3 and Allan Lipton1a

1 The M.S. Hershey Medical Center, Hershey, PA 17033.

2 Veterans Administration Medical Center, Lebanon, PA 17042.

3 Bayer Corporation, Tarrytown, NY 10591.

aAddress correspondence to this author at: The M.S. Hershey Medical Center, Department of Medicine, Division of Hematology/Oncology HO46, 500 University Dr., PO Box 850, Hershey, PA 17033.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Serum HER-2/neu antigen concentrations have been reported to correlate with increased tumor volume in patients with breast cancer. We measured serum CA 15-3, a surrogate marker of disease burden, and correlated serum CA 15-3 with serum HER-2/neu and analyzed the association of both markers with clinical outcomes.

Methods: Pretreatment serum samples from 566 patients were retrospectively analyzed from 2 phase III clinical trials of estrogen receptor-positive (ER+), ER-/progesterone receptor-positive, or ER status unknown metastatic breast cancer patients randomized in two similar studies to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole). The extracellular domain of the HER-2/neu (c-erbB-2) oncogene and serum CA 15-3 were measured by ELISA on the Bayer Immuno 1.

Results: Serum HER-2/neu protein was increased in 168 patients (30%), and CA 15-3 was increased in 337 (60%) patients. Serum CA 15-3 and HER-2/neu were weakly correlated (r = 0.39; P <0.0001). The clinical benefit (complete responses plus partial responses plus stable disease) of endocrine therapy was significantly lower in patients with increased serum HER-2/neu. When adjusted for serum HER-2/neu, serum CA 15-3 was not predictive of response rates. The median time to progression was shorter in patients with increased serum HER-2/neu (89 days) compared with patients with normal serum HER-2/neu (176 days). Survival was significantly shorter in patients with increased serum HER-2/neu (513 vs 869 days; P <0.0001) or increased serum CA 15-3 (689 vs 939 days; P <0.0001). This observation was confirmed by multivariate analysis.

Conclusions: Serum HER-2/neu is a significant independent predictive and prognostic factor in hormone receptor-positive metastatic breast cancer, even when adjusted for tumor burden as measured by CA 15-3. The combination of increased serum HER-2/neu and increased serum CA 15-3 predicts a worse prognosis than does increased CA 15-3 alone.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
There is significant heterogeneity in the survival of breast cancer patients. This fact was highlighted by Rahman et al. (1), who reported that patients with favorable characteristics had a significantly longer survival than did patients with unfavorable characteristics who participated in similar studies. There are numerous reports on predictive and prognostic factors and their correlation with response rate, time to progression (TTP),1 and overall survival. Traditional factors that been shown to be predictive of response in patients receiving hormone therapy are receptor status, dominant site of metastasis, and menopausal status (2)(3). In addition, other variables, including age, number of metastatic sites, performance status, and disease-free interval, have all been shown to be prognostic factors for overall survival (2)(4).

Several studies have correlated the overexpression of the HER-2/neu (c-erbB-2) oncogene with poor prognosis in breast cancer patients. The HER-2/neu protooncogene encodes a 185-kDa transmembrane glycoprotein growth factor receptor (p185-HER-2/neu) that contains an extracellular domain and has intracellular tyrosine kinase activity (5). Amplification of the HER-2/neu gene and overexpression of its protein was discovered in a human breast cancer cell line (6). Sequencing of the HER-2/neu gene revealed a distinct gene with strong homology to the epidermal growth factor receptor (7). Since that time, numerous reports have shown that HER-2/neu gene amplification or protein overexpression is evident in 10–40% of primary human breast cancers (8)(9), with an overall average of 20% from a combined total of almost 3000 patients (10).

Many cell surface transmembrane receptors are shed. Soluble forms of the insulin, epidermal growth factor receptor, interleukin-2, and tissue necrosis factor receptors have been demonstrated in cell culture supernatants and in human serum and urine. A soluble immunoreactive form of the HER-2/neu receptor has also been detected in the sera of nude mice that bear SK-0V-3 ovarian cancer or MDA-MB-361 breast cancer xenografts (11). These antigen concentrations correlated with both overexpression of the HER-2/neu protein and increased tumor volume. Subsequently, we and other investigators have reported increased soluble HER-2/neu in the plasma or serum of 20–25% of patients with metastatic breast cancer (12)(13)(14). Many reports have shown that increased serum HER-2/neu is associated with a worse prognosis. However, previous reports did not address an important question: Are increased serum HER-2/neu concentrations only a surrogate marker of the tumor burden, or do they reflect the inherent aggressiveness of the underlying tumor?

Several studies have shown that metastatic breast cancer patients with a high disease burden have a poorer prognosis (2)(4). It is difficult to quantify disease burden with imaging studies, and some patients have evaluable but not measurable disease. Serum CA 15-3 is used as a surrogate marker of disease bulk to monitor metastatic breast cancer patients undergoing treatment and for the preclinical detection of tumor recurrence. We have previously shown that increased serum HER-2/neu is associated with both a decreased response rate and shorter time of survival (15). We performed the present study to determine whether serum HER-2/neu concentrations are a measure of disease bulk only or whether they also reflect both disease bulk and the biology of disease, i.e., tumor aggressiveness, as has been reported in animal models (11). In the present study, we evaluated serum HER-2/neu and CA 15-3 concentrations to assess the predictive and prognostic potential of serum HER-2/neu when adjusted for disease bulk as measured by the serum CA 15-3 concentration.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
patient population
The sera for this retrospective analysis were obtained from 566 patients with metastatic breast cancer on the day of entry into two phase III clinical trials of second-line hormone therapy for metastatic breast cancer. The two trials (299 and 267 patients, respectively) compared the second-generation aromatase inhibitor fadrozole with megestrol acetate.

Patients in both studies were between 35 and 92 years of age and had a Karnofsky performance rating of at least 50% or Eastern Cooperative Oncology Group (ECOG) performance status of 0–3. All patients were required to be postmenopausal as defined by the following criteria: women >=50 years of age who had not menstruated during the preceding 12 months or had castrate follicle-stimulating hormone concentrations (>40 IU/L); those younger than 50 years who had castrate follicle-stimulating hormone concentrations; or those who had undergone a bilateral oophorectomy. All patients had received one previous hormone therapy for metastatic disease. Patients could have received one previous adjuvant chemotherapy or one previous adjuvant hormone therapy.

study design
Both studies were multicenter, randomized, parallel-group, double-blind trials. Drugs were supplied using the double-dummy technique. Patients who met admission criteria were randomized to receive the following: in study 1, megestrol acetate (40 mg orally four times a day) plus placebo (matching fadrozole) or fadrozole (1 mg orally twice a day) plus placebo (matching megestrol acetate). Study 2 was identical to study 1.

efficacy assessments
Tumor response in each study was assessed by appropriate measurements or x-rays every 3 months. Complete response (CR) required the complete disappearance of all disease for at least 4 weeks. Partial response (PR) was defined as a 50% decrease in the sum of the product of two diameters of all measurable lesions and at least stabilization of all nonmeasurable lesions maintained for a minimum of 4 weeks. Stable disease consisted of a <50% decrease in the sum of the products of two diameters of all measurable lesions that was maintained for at least 6 months. Progressive disease was defined as a >25% increase in the sum of the product of two diameters of one or more measurable tumors or an unequivocal increase of new lesions. Patients with clinical benefit were defined as those responding (CR + PR) plus those with stable disease for at least 6 months.

TTP, duration of response, and survival were calculated from the date of randomization. TTP represented the time to objective disease progression or death. Duration of response in patients who achieved CR, PR, or stable disease for >=6 months was also defined as the time from randomization to the time of first observation of objective progression. Survival was the time from the date of randomization to death.

serum preparation
Blood was collected by forearm venipuncture within 14 days before initiation of second-line hormone therapy. The blood was then centrifuged at 500g for 10 min at room temperature. The serum supernatant was then collected, aliquoted, and stored at -70 °C.

HER-2/neu elisa assay
Serum HER-2/neu was measured using an automated HER-2/neu assay (Bayer Immuno 1) that has been approved by the US Food and Drug Administration. Serum CA 15-3 was assayed using the Bayer Immno 1 CA 15-3 assay. All patient samples were analyzed in a blinded fashion, i.e., without knowledge of the clinical outcome of individual patients.

statistical methods
The cutoff point of 15 µg/L (15 ng/mL; mean + 2 SD of 211 healthy control women) was used for serum HER-2/neu, and a cutoff of 38.5 kilounits/L (38.5 units/mL; nonparametric 95th percentile of healthy control women) was used for serum CA 15-3. These cutpoints were used as recommended by the manufacturer (Bayer Diagnostics) for routine clinical use. The {chi}2 test was applied to ascertain statistically significant differences. Two-way frequency tables were constructed to describe the categorical variables, such as increased serum HER-2/neu and response status. More sophisticated analysis of categorical variables consisted of logistic regression analysis in which the response was coded as 1 (progressive disease) or 0 (CR, PR, or stable disease).

Variables used in the logistic regression for the binary outcome and proportional hazards regression for the time-to-event outcomes were age, HER-2/neu, CA 15-3, receptor status, disease-free interval, performance status, visceral status, and adjuvant chemotherapy. Bonferroni adjustments were made for multiple comparisons for those predictor variables with more than two levels.

For further analysis, patients were divided into four groups. The first group consisted of patients who did not have an increase in serum HER-2/neu or CA 15-3. This group was the index group to which the other three groups were compared. The second group consisted of patients who had increased serum CA 15-3 only. The third group consisted of patients who had increased serum HER-2/neu only, and the fourth group consisted of patients who had increases in both serum HER-2/neu and serum CA 15-3. These groups were modeled on survival time, time to disease progression, and response, without adding other predictors to the model.

Kaplan–Meier survival curves were graphed to visually compare time-to-event variables, such as time to disease progression, duration of response, and survival time, for the groups with and without increased markers. The log-rank test was used to compare these survival curves. All calculations were performed using PROC FREQ, PROC CORR, PROC NPAR1WAY, PROC Logistic, PROC Lifetest, and PROC PHREG in Ver. 8.2 of SAS (SAS Institute).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
patient characteristics
A total of 168 patients (30%) with metastatic breast cancer had increased serum HER-2/neu, and 398 patients (70%) had values within the reference interval. Baseline patient characteristics are described in Table 1 . There were no significant differences between the group with increased serum HER-2/neu and the group without increased HER-2/neu according to age, race, disease-free interval, adjuvant chemotherapy, ECOG performance status, and estrogen receptor (ER)/progesterone receptor (PgR) status. Patients with increased serum HER-2/neu had a higher percentage of visceral metastases than did those without increased HER-2/neu. Patients with increased serum HER-2/neu weighed more than those without increased HER-2/neu.


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  		Table 1. Distribution of serum HER-2/neu by clinical characteristics.

The cutoff of 38.5 kilounits/L (nonparametric 95th percentile) for CA 15-3 was derived from the sera of 202 healthy postmenopausal women. When we used this cutoff, 337 (60%) of the patients had increased serum CA 15-3.

Serum HER-2/neu results were correlated with serum CA 15-3 concentrations as continuous variables. There was a weak but significant correlation between the two markers, with a correlation coefficient of 0.39 (P <0.0001; Fig. 1 ). Of the 168 patients with increased serum HER-2/neu, 135 (80%) also had increased CA 15-3 (Table 2 ). Conversely, 202 of 398 (51%) of the patients who did not have increased serum HER-2/neu had increased serum CA 15-3 (Table 2 ).



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  		Figure 1. Scatter plot showing correlation of serum HER-2/neu with serum CA 15-3.

Serum concentrations of the two markers were weakly correlated (r = 0.39).


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  		Table 2. Correlation of serum HER-2/neu and serum CA 15-3 concentrations.1

We evaluated the tumor burden of metastatic disease as reflected by the number of sites involved and correlated these with the serum marker concentration. In this study, 244 of 566 (43%) of the patients had more than one site of metastatic disease. The correlation of number of metastatic sites to the marker concentrations is shown in Table 3 . There was a trend favoring increased number of metastatic sites in the group of patients with both increased marker concentrations.


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  		Table 3. Correlation of number of metastatic sites with serum markers.

response to treatment
Response to second-line endocrine therapy was determined for all 566 patients. In this study, the response rate (CR + PR + stable disease) to endocrine therapy was 38% (217 of 566 patients; Table 4 ). In the patients who had increased serum HER-2/neu, the response rate in univariate analysis was significantly lower compared with patients who did not have increased concentrations of the marker (P <0.0001). In the analysis of the four groups, patients who had increased serum HER-2/neu and did not have increased CA 15-3 had marginally lower response rates compared with patients in whom neither HER-2/neu nor CA 15-3 was increased (P = 0.064). Patients with both serum factors increased had lower response rates compared with patients in whom neither marker was increased (P = 0.0004). In the multivariate model, increased CA 15-3 was not predictive of response to endocrine therapy (Table 5 ).


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  		Table 4. Response to second-line endocrine therapy according to serum HER-2/neu and serum CA 15-3 status.


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  		Table 5. Multivariate analysis for clinical benefit, TTP, and overall survival.

The duration of clinical response for patients who responded (CR + PR + stable disease) was shorter in patients with increased serum HER-2/neu compared with patients who did not have increased serum HER-2/neu. The median duration of response was 349 days in the patients with increased serum HER-2/neu and 521 days in the patients with serum HER-2/neu concentrations within the reference interval (P <0.0001).

ttp
Patients with increased serum HER-2/neu had a significantly shorter TTP (P <0.0001). The median TTP for patients with increased serum HER-2/neu was 89 days vs 176 days for patients who did not have increased serum HER-2/neu (P <=0.0001). A Kaplan–Meier plot of TTP is presented in Fig. 2 and shows the interaction between the two markers. There was no significant effect of increased serum CA 15-3 on TTP in multivariate analysis (Table 5Up ).



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  		Figure 2. Kaplan–Meier plot of TTP as a function of pretreatment serum markers.

(- - - -), HER-2/neu- <=15 µg/L and CA 15-3 <=38.5 kilounits/L; (· · · ·), HER-2/neu- <=15 µg/L and CA 15-3 >38.5 kilounits/L; (- - -), HER-2/neu- >15 µg/L and CA 15-3 <=38.5 kilounits/L; (——–), HER-2/neu- >15 µg/L and CA 15-3 >38.5 kilounits/L.

survival
Survival was defined as the period from the start of second-line hormone treatment with either megestrol acetate or fadrozole until death. At the end of the trial, 368 of 566 patients (65%) had died. Patients with increased serum HER-2/neu had significantly shorter survival times (513 vs 869 days; P <0.0001), as did patients with increased serum CA 15-3 (689 vs 939 days; P <0.0001). We studied the interaction of the two markers, and the results are shown in Fig. 3 . Patients who had increased CA 15-3 but did not have increased HER-2/neu had significantly shorter survival times than did patients in whom neither marker was increased. In addition, the combination of increased serum HER-2/neu and increased serum CA 15-3 predicted a poorer prognosis compared with increased CA 15-3 alone, without other predictors in the model (Fig. 3 ).



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  		Figure 3. Kaplan–Meier plot of survival from start of second-line hormone therapy as a function of pretreatment serum markers.

(- - - -), HER-2/neu- <=15 µg/L and CA 15-3 <=38.5 kilounits/L; (· · · ·), HER-2/neu- <=15 µg/L and CA 15-3 >38.5 kilounits/L; (- - -), HER-2/neu- >15 µg/L and CA 15-3 <=38.5 kilounits/L; (——–), HER-2/neu- >15 µg/L and CA 15-3 >38.5 kilounits/L.

In multivariate analysis, increased serum CA 15-3 and increased serum HER-2/neu were both independently associated with a shorter survival (Table 5Up ).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The HER-2/neu status of a patient is usually evaluated by immunohistochemistry (IHC) of the primary breast cancer specimen. There is a subjective element in grading of IHC, and this has been the subject of many ongoing debates. It has been shown that 75% of the patients who have 2+ HER-2/neu overexpression by IHC do not have gene amplification by fluorescent in situ hybridization (16). The extracellular domain of the HER-2/neu oncoprotein is shed into the blood and may be detected in the serum. Bayer Diagnostics has developed an automated ELISA assay (Bayer Immuno 1) for measuring circulating concentrations of the HER-2/neu oncoprotein. Some of the advantages of this method are that it is reproducible, quantitative, and objective and blood is routinely collected in the physician’s office before administration of chemotherapy. In addition, blood collection provides a real-time analysis of the patient’s serum HER-2/neu status at the time clinical decisions are made concerning therapy for metastatic disease.

The currently published literature suggests that circulating HER-2/neu antigen concentrations are associated with tumor burden, HER-2/neu overexpression, and receptor activation. In MDA MB-361 xenografts of nude mice, it has been shown that serum antigen concentrations correlated with both overexpression of the HER-2/neu protein and increased tumor volume (10). Molina et al. (17) have shown that cleavage of the extracellular domain of HER-2/neu receptor leads to increased phosphorylation of the intracellular tyrosine kinase. This observation suggests that circulating antigen concentrations are not only a marker of tumor overexpression of HER-2/neu, but they may also be indicative of the degree of receptor activation. Increased serum HER-2/neu is seen with increasing stage of disease (18). On the basis of these observations, the question has been raised whether the serum HER-2/neu concentration reflects tumor aggressiveness or is simply a surrogate marker of disease bulk. A previous study of 378 patients in the pivotal Herceptin metastatic breast cancer trials showed a significant overall correlation of 74% of patients with increased serum HER-2/neu who had positive HER-2/neu IHC of the primary tumor (84% correlation with IHC of 3+, and 44% correlation with IHC of 2+) (19).

In this study, the automated assay for HER-2/neu (Bayer Immuno 1) was used to determine the serum concentrations of shed HER-2/neu receptor. Serum CA 15-3 (a surrogate marker of disease bulk) correlated with serum HER-2/neu, and the association of both markers with clinical outcomes was analyzed. Our study shows that serum CA 15-3 was not a predictive factor for response rate in the multivariate model. However, serum HER-2/neu remained a predictive factor for response rate in both univariate and multivariate models (Table 5Up ), a result that was identical for TTP. There are conflicting reports about the value of HER-2/neu overexpression in predicting resistance to endocrine therapy (15)(20)(21). Our results support the recent conclusion of Hamilton and Piccart (22) that HER-2/neu is the most promising molecular marker for predicting decreased response to hormonal therapy in breast cancer.

Tumor burden as reflected by number of metastatic sites and serum CA 15-3 concentrations has previously been shown to be an adverse prognostic factor (23). In our study, increased serum CA 15-3 predicted worsened survival in both univariate and multivariate models (Table 5Up ). Increased serum HER-2/neu also predicted a worsened prognosis. The interaction of the two markers with regard to effect on survival is shown in Fig. 3Up . Increased serum CA 15-3 alone was associated with a poorer prognosis than when neither marker was increased. Patients with increased serum HER-2/neu and serum CA 15-3 had a shorter survival than did patients with an increased serum CA 15-3 alone.

In conclusion, this study shows that serum HER-2/neu remains a significant independent predictive and prognostic factor in hormone receptor-positive metastatic breast cancer even when adjusted for tumor burden as measured by CA 15-3. These results strengthen our recent conclusion that patients with increased serum HER-2/neu have a decreased response to hormone therapy and should be considered for combined treatment with both hormonal and HER-2/neu blockade, i.e., aromatase inhibitors and Herceptin (24). Increased serum CA 15-3 was not predictive of response to endocrine therapy but did predict a worsened survival. Furthermore, the combination of increased serum HER-2/neu and increased serum CA 15-3 predicted a poorer prognosis compared with increased CA 15-3 alone.


   Footnotes
 
1 Nonstandard abbreviations: TTP, time to progression; ECOG, Eastern Cooperative Oncology Group; CR, complete response; PR, partial response; ER, estrogen receptor; PgR, progesterone receptor; and IHC, immunohistochemistry.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Potential Clinical Utility of Serum HER-2/neu Oncoprotein Concentrations in Patients with Breast Cancer
Clin. Chem., October 1, 2003; 49(10): 1579 - 1598.
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 The OncologistHome page
J. S. Ross, J. A. Fletcher, G. P. Linette, J. Stec, E. Clark, M. Ayers, W. F. Symmans, L. Pusztai, and K. J. Bloom
The HER-2/neu Gene and Protein in Breast Cancer 2003: Biomarker and Target of Therapy
Oncologist, August 1, 2003; 8(4): 307 - 325.
[Abstract] [Full Text] [PDF]

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 JCOHome page
M. Beltran, R. Colomer, A Lipton, S.M. Ali, and K. Leitzel
Does HER-2 Status Predict Only a Decreased Response to Hormone Therapy in Advanced Breast Cancer, or Does It Also Predict the Extent of Metastatic Disease?
J. Clin. Oncol., December 1, 2002; 20(23): 4605 - 4606.
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