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Clinical Cancer Research Vol. 8, 3454-3460, November 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Prognostic and Predictive Value of Epidermal Growth Factor Receptor in Recurrent Breast Cancer

Shinichi Tsutsui1, Akemi Kataoka, Shinji Ohno, Shigeru Murakami, Junko Kinoshita and Yoichi Hachitanda

Department of Breast Surgery, Beppu National Hospital, Beppu 874-0011 [S. T.], and Departments of Breast Surgery [A. K., S. O., S. M., J. K.] and Pathology [Y. H.] National Kyushu Cancer Center, Fukuoka, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The prognostic and predictive value of epidermal growth factor receptor (EGFR) expression was evaluated in patients with recurrent breast cancer.

Experimental Design: The immunohistochemical expression of EGFR was analyzed in 241 patients with recurrent breast cancer.

Results: EGFR expression was positive in 87 of 241 (36%) patients with recurrent breast cancer, whereas the EGFR expression inversely correlated with the estrogen receptor (ER) status. The patients with positive EGFR expression had a significantly worse postrelapse survival than those with a negative EGFR expression, whereas EGFR expression also had a postrelapse prognostic significance in patients with a positive ER status. A multivariate analysis indicated EGFR expression to be an independently significant factor for postrelapse survival, whereas a multivariate analysis in which the ER status was added to variables indicated that ER status but not EGFR expression to be an independently significant factor. There was a significant difference between positive and negative EGFR expression in the treatment response of 82 patients who received hormonal therapies and 374 patients who received chemotherapies, whereas a multivariate analysis indicated the responses to the first-line treatment and EGFR expression to be independently significant factors for postrelapse survival.

Conclusions: EGFR expression had prognostic significance in recurrent breast cancer, whereas its prognostic value was not independent of the ER status. In addition, the EGFR expression was suggested to be related to the responses to hormonal therapy and chemotherapy, whereas the EGFR expression had an additional prognostic value that was independent of the treatment response.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The axillary lymph node status at primary surgery is still the most powerful prognostic factor for the postoperative survival of patients with breast cancer (1 , 2) , whereas established prognostic factors for postrelapse survival are dominant sites of recurrence and the response to the systemic therapies (3) . On the other hand, the parameters indicating the biological characteristics of breast cancer cells, especially in those related to the response to systemic therapies, are suggested to be involved in the whole course, consisting of postoperative and postrelapse courses, of patients with breast cancer. In addition, because numerous data on the function of these biological parameters have been accumulated recently in experimental studies, it is very important to evaluate the prognostic and predictive value of these biological parameters in clinical studies. There is, however, still little clinical data on the biological parameters for recurrent breast cancer, whereas only ER2 status has been demonstrated as an established postrelapse prognostic factor for recurrent breast cancer (3, 4, 5, 6) .

EGFR is a Mr 170,000 membrane glycoprotein that contains ligand binding sites in its extracellular domain and tyrosine-specific protein kinase activity and autophosphorylation sites in its cytoplasmic domain (7) . The structure and signaling pathway of EGFR and EGF, which is a major ligand to EGFR, have both been evaluated in many experimental studies, and various aspects have thus been elucidated (8, 9, 10, 11, 12, 13) . In clinical studies, EGFR has been also shown to be one of the postoperative prognostic factors for breast cancer (14, 15, 16, 17, 18, 19) ; however, there have been few studies on the prognostic value of EGFR for recurrent breast cancer (20 , 21) . We demonstrated previously the postoperative prognostic value of EGFR expression in 1029 patients with primary breast cancer (2) and also the consistency of EGFR expression between primary and recurrent breast cancers (22) . In the present study, the prognostic and predictive value of EGFR expression was investigated in 241 patients with recurrent breast cancer.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
This study comprised 241 women who underwent treatment for recurrent breast cancer between 1992 and 1999 at the National Kyushu Cancer Center Hospital. All patients had undergone primary surgery for breast cancer without any evidence of distant metastasis and then were clinically determined to have recurrent breast cancer. Clinicopathological information recorded at the time of the first clinical manifestation of recurrent breast cancer included age, type of operation performed, postoperative adjuvant therapies, DFI, tumor size and axillary lymph node metastasis at primary surgery, dominant sites of recurrence, and ER status. An ER assay was performed using the enzyme immunoassay method with a cutoff level for positivity of 5 fmol/mg protein, and the ER status was available for 239 patients.

Immunohistochemical Analysis of EGFR.
The EGFR expression was evaluated by the immunohistochemical method as described previously (2 , 22) . Briefly, specimens of each breast cancer were frozen in liquid nitrogen immediately after either primary surgery or a biopsy. Frozen samples were cut into 10–15-µm sections and fixed in cold acetone for 30 min. After rinsing in distilled water, the sections were washed in PBS and then incubated at 4°C overnight with primary EGFR monoclonal antibody (Kyokutou Seiyaku, Tokyo, Japan). After rinsing in three changes of PBS, the sections were incubated with peroxidase-conjugated antimouse immunoglobulin (Nichirei, Tokyo, Japan) at room temperature for 30 min. Staining was visualized with 3,3-diaminobenzidine, followed by washing in distilled water and counterstaining with hematoxylin. The expression of EGFR was generally found on whole cancer cells (2 , 22) . Because it was difficult to distinguish the expression of EGFR in the cytoplasm from the expression of EGFR on the membrane, the tumors exhibiting definite staining of the cancer cells were considered to be positive for EGFR (2 , 22) . The final determinations for the immunohistochemical expression of EGFR were made by one pathologist (Y. H.) without any knowledge of the clinical course of each patient.

One hundred seventy samples were obtained from the primary breast cancer, and 103 samples were obtained from the recurrent breast cancer, whereas both samples from the primary and recurrent breast cancers were obtained from 32 patients. The 103 recurrent sites on which a biopsy was performed consisted of 38 local recurrences, 58 lymph node, 4 contralateral breast, 2 skin, and 1 bone.

Statistical Analysis.
The {chi}2 test and Student’s t test were used to investigate the significance of the relationships between individual variables. The survival curves were estimated using the method of Kaplan and Meier, and the difference in the survival curves was compared by the log-rank test. A multivariate analysis was performed by Cox’s regression model. Ps of <0.05 were regarded as statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
EGFR Expression between the Primary and Recurrent Lesions.
The EGFR expression was positive in 71 of 170 (42%) cases obtained from primary surgery specimens, whereas the EGFR expression was positive in 28 of 103 (27%) cases obtained from biopsy specimens for recurrent breast cancer. Because a concordance of the immunoreactivity of EGFR expression between the primary and recurrent lesions was observed in 28 of 32 (88%) cases in which the EGFR expression was determined on both primary and recurrent lesions (22) , EGFR expression for recurrent breast cancer in the 138 cases in which the EGFR expression was determined only in the primary lesions was considered to be the same as the findings of the primary lesions. As a result, EGFR expression was considered to be positive in 87 (36%) and negative in 154 (64%) of 241 patients with recurrent breast cancer. The ER status for recurrent breast cancer was also considered to be the same as the findings of the primary lesions in the 162 cases in which the ER status was determined only in the primary lesions.

Cliniopathological Factors of Patients with Recurrent Breast Cancer.
The relationships between the clinicopathological factors and EGFR expression are shown in Table 1Citation . Significant differences were observed in the DFI and dominant sites of recurrence between a positive and negative finding of EGFR expression. A closely inverse correlation was observed between the EGFR expression and ER status. EGFR expression was positive in 68 of 109 (62%) cases with a negative ER status, whereas EGFR expression was positive in 17 of 130 (13%) cases with a positive ER status (P < 0.0001). The relationships between the clinicopathological factors and ER status are also shown in Table 1Citation . Significant differences were also observed in the DFI and dominant sites of recurrence between a positive and negative ER status.


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  		Table 1 Relationship between the clinicopathological factors and either EGFR expression or ER status

 
Univariate Analyses for Postrelapse Survival.
Fig. 1Citation shows the postrelapse survival of the 241 patients according to the EGFR expression and ER status. The patients with a positive EGFR expression had a significantly (P < 0.0001) worse postrelapse survival than those with a negative EGFR expression, whereas the patients with a negative ER status had also a significantly (P < 0.0001) worse postrelapse survival than those with a positive ER status. Fig. 2Citation shows the postrelapse survival according to the EGFR expression in 130 patients with a positive ER status and in 109 patients with a negative ER status. The patients with a positive EGFR expression had a significantly (P = 0.0021) worse postrelapse survival than those with a negative EGFR expression in the positive ER patient group, whereas no difference (P = 0.3021) was observed in postrelapse survival between a positive and negative EGFR expression in the negative ER patient group.



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  		Fig. 1. Postrelapse survival curves according to the EGFR expression (above) and ER status (below).

 


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  		Fig. 2. Postrelapse survival curves according to the EGFR expression in the patients with a positive ER (above) and negative ER (below) status.

 
Multivariate Analyses for Postrelapse Survival.
A multivariate analysis was performed to determined the contributing factors for postrelapse survival (Table 2)Citation . A multivariate analysis was performed on variables including age, tumor size, lymph node metastasis, primary surgical operation, adjuvant therapies, DFI, dominant sites of recurrence and EGFR expression. A multivariate analysis was also performed on the variables to which the ER status was added. A first multivariate analysis indicated the visceral recurrence and EGFR expression to be independently significant factors for the postrelapse survival. A second multivariate analysis, however, indicated visceral recurrence and ER status to be independently significant factors for postrelapse survival, whereas EGFR expression was not an independently significant factor for postrelapse survival.


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  		Table 2 Multivariate analysis for the postrelapse survival in patient with recurrent breast cancer

 
Response to Systemic Treatments According to EGFR Expression.
Overall, 456 systemic therapies, in which the treatment response was assessable, were performed on 199 of 241 patients as the first to fourth-line treatments. First-, second-, third-, and fourth-line treatments were performed in 199, 132, 86, and 39 patients, respectively, and the total of 456 systemic therapies consisted of 82 hormonal therapies on 69 patients and 374 chemotherapies, including 169 chemotherapies combined with hormonal therapy of which the majority were medroxyprogesterone acetate, on 183 patients (Table 3)Citation . Table 4Citation shows the response to systemic treatments according to the EGFR expression. In 456 whole treatments on 199 patients, there was a significant difference in the treatment response (P = 0.0014) and the objective response rate (P = 0.0075) between the cases with positive and negative EGFR expression. In 82 hormonal therapies on 69 patients, a significant difference in the treatment response (P = 0.0209) was observed between the cases with positive and negative EGFR expression, whereas the difference in the objective response rate was not statistically significant. In 374 chemotherapies on 183 patients, there was a significant difference in the treatment response (P = 0.0196) and the objective response rate (P = 0.0061) between the cases with positive and negative EGFR expression.


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  		Table 3 Systemic treatments for recurrent breast cancer

 

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  		Table 4 Response to systemic treatments according to EGFR expression

 
The response to systemic treatments was also evaluated according to the combination of the EGFR expression and ER status (Table 4)Citation . In 452 whole treatments, the cases with an EGFR-negative/ER-positive tumor had a better treatment response, whereas the cases with an EGFR-positive/ER-negative tumor had a worse treatment response, whereas a similar effect was also found in 370 chemotherapies. The response to hormonal therapies was better in the cases with a positive ER status than those with a negative ER status. In 65 hormonal therapies for ER positive cases, no difference was observed between the cases with positive and negative EGFR expression, whereas the number of cases with EGFR-positive/ER-positive tumors was only 6.

Prognsotic Value of EGFR Expression in Relation to Treatment Response.
To clarify the prognostic value of the EGFR expression in relation to the treatment response, a multivariate analysis was performed on variables including the response to first-line treatment. A multivariate analysis indicated that the three variables (CR, PR and no change; versus progressive disease) in the response to first-line treatment were independently significant factors for postrelapse survival and that EGFR expression was also an independently significant factor for postrelapse survival (P = 0.0016). In addition, the multivariate analysis to which the ER status was added indicated the ER status to be an independently significant factor for postrelapse survival (P = 0.0104), whereas EGFR expression was not a significant factor for postrelapse survival (P = 0.2054).

Prognostic Value of EGFR Expression in Patients Who Responded to First-Line Treatments.
To clarify the prognostic value of EGFR expression in the patients who showed responses to first-line treatments, the times to progression for first-line treatment and postrelapse survival according to the EGFR expression were analyzed in 77 patients in whom the response to first-line treatment was CR or PR (Fig. 3)Citation . The patients with a positive EGFR expression had a significantly (P = 0.0008) shorter time to progression and a significantly (P < 0.0001) worse postrelapse survival than those with a negative EGFR expression.



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  		Fig. 3. Time-to-progression curves (above) and postrelapse survival curves (below) according to EGFR expression in the patients in which the responses to the first-line treatment was CR or PR.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
There have been a few studies on the postrelapse prognostic value of EGFR expression for recurrent breast cancer (20 , 21) . One of the reasons why few studies exist on recurrent breast cancer is that it is not easy to obtain an adequate sample size to evaluate the biological parameters of recurrent breast cancer. If the biological parameters of the breast cancer at primary surgery are used as that of recurrent breast cancer, a long observation period is necessary. On the other hand, the sampling on recurrent breast cancer is usually restricted to the sites of soft tissue recurrence. We have analyzed immunohistochemical expression of EGFR on fresh-frozen sections from 1029 patients who underwent primary surgery for breast cancer from 1992 to 1998 (2) . The 170 samples in the present study were obtained from the patients who suffered a relapse in these 1209 patients. In addition, the samples of recurrent breast cancer were also obtained from 103 patients with recurrent breast cancer. The positive rate of EGFR expression in the samples obtained from recurrent breast cancer was lower than that obtained from primary breast cancer of the patients who suffered a relapse of breast cancer. The reason for the lower rate of EGFR expression in the samples obtained from recurrent breast cancer is that the majority of biopsied sites tended to be areas of soft tissue recurrence. We demonstrated previously, however, a concordance of EGFR expression between the primary and recurrent lesions in 27 of 30 (90%) patients and indicated the consistency of EGFR expression during tumor progression from the primary lesion to the recurrent lesion (22) . In the present study, therefore, the EGFR expression of recurrent breast cancer for the patients, in which the samples of the recurrent breast cancer have not been obtained, was considered to be the same as that for primary breast cancer.

A close inverse correlation between EGFR and ER has been demonstrated in breast cancer specimens (2 , 14, 15, 16, 17, 18, 19 , 23) as well as breast cancer cell lines (24) . Recently, there is an increasing body of evidence to indicate cross-talk between EGFR and ER signaling pathways (8) . Estrogen was demonstrated to regulate EGFR expression in breast cancer cell lines (9 , 10) , whereas the EGFR signaling pathway components have been shown to involve the ER signaling pathway (8) . The transfection of EGFR cDNA into estrogen-dependent breast cancer cells leads to anti-estrogen resistance and a stable hormone-independent phenotype (11) . ER protein has also been shown to be subject to phosphorylation and activation by EGF (12) , which could subsequently initiate an estrogen response element-mediated gene expression (13) . Accumulated evidence in experimental studies suggests the inverse relationship between EGFR and ER to be functionally significant and not simply coincidental. The results based on a multivariate analysis in the present study, indicating the ER status to be a more powerful postrelapse prognostic factor than EGFR expression, may merely mean that EGFR expression is an indicator of a negative ER. However, the prognostic significance of EGFR expression demonstrated in the positive ER patient group indicated that EGFR expression has additional prognostic value in a positive ER status. Further progress in understanding the cross-talk between the EGFR and ER signaling pathways is necessary to satisfactorily explain the results shown by a multivariate analysis in the present study.

There have been several clinical studies on the relationship between EGFR expression and the response to hormonal therapy for breast cancer (20 , 21 , 25, 26, 27) . Nicholson et al. (20) demonstrated that 19 of 44 (43%) patients with a negative EGFR expression were responders to hormonal therapy, whereas 7 of 62 (11%) patients with a positive EGFR expression were responders to hormonal therapy. The response rate to hormonal therapy according to EGFR expression in the present study seems to correlate with these previous studies; however, there were no differences in the response rate to hormonal therapy according to the EGFR expression in the patient groups stratified by ER status. Nicholson et al. (20) also demonstrated that 18 of 41 (44%) patients with a negative EGFR expression were hormone sensitive, whereas 6 of 25 (24%) patients with a positive EGFR expression were hormone sensitive in the patient group with a positive ER status. The above-mentioned experimental evidence about the cross-talk between the EGFR and ER signaling pathways will also help account for the involvement of EGFR in hormone unresponsiveness (8) . Regarding chemotherapy for recurrent breast cancer, few clinical data exist on the relationship between the EGFR expression and the response to chemotherapy (28) . The transfection of EGFR into a ZR75 cell line resulted in a reduced sensitivity to doxorubicin, vinblastine, cisplatin, and 5-fluorouracil (29) . Mendelsohn and Fan (30) described that an alteration of signal transduction pathways in erbB family receptors can influence the sensitivity of a number of cell lines to chemotherapeutic agents and also that the mechanisms explaining these effects have yet be determined. The present study was a retrospective study, and the hormonal therapies and chemotherapies consisted of various regimens. The data shown in the present study suggested that the patients with a positive EGFR expression did not respond to hormonal therapy or chemotherapy for recurrent breast cancer, whereas EGFR expression also had additional prognostic value that was independent of the response to the systemic treatments.

In conclusion, the present study indicated EGFR expression to have prognostic significance in recurrent breast cancer, whereas a multivariate analysis indicated ER status to be a more powerful prognostic factor than EGFR expression. EGFR expression, however, had additional prognostic value in a positive ER status. Further progress in understanding the cross-talk between the EGFR and ER signaling pathways will help explain the results demonstrated in multivariate analyses. In addition, the patients with a positive EGFR expression tended to not respond to hormonal therapy and chemotherapy for breast cancer, whereas EGFR expression had an additional prognostic value that was independent of the response to first-line treatment. Clinical trials to evaluate the effect of EGFR expression on the response to hormonal therapy and chemotherapy for recurrent breast cancer are therefore called for in the future.


   ACKNOWLEDGMENTS
 
We thank Tomoyuki Suzaki and Yuji Ogino of Sumikin Bioscience for expert technical assistance and also thank Brian Quinn for review of the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Department of Breast Surgery, Beppu National Hospital, 1473 Oaza-Uchikamado, Beppu 874-0011, Japan. Fax: 81-977-67-5766. Back

2 The abbreviations used are: ER, estrogen receptor; EGFR, epidermal growth factor receptor; DFI, disease-free interval; CR, complete response; PR, partial response. Back

Received 3/12/02; revised 6/17/02; accepted 7/19/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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