© 2005 European Society for Medical Oncology
Impact of EGFR expression on colorectal cancer patient prognosis and survival
,*1 Département d'Oncologie Médicale, Hôpital Pitié-Salpétrière, Paris; 2 Département d'Anatomopathologie, Hôpital Avicenne, Bobigny; 3 Département de Radiothérapie et Statistique, Hôpital Européen Georges Pompidou, Paris; 4 Département d'Oncopharmacologie, Centre Antoine Lacassagne, Nice; 5 Département de Gastro-Entérologie, Hôpital Avicenne, Bobigny; 6 Département de Chirurgie Viscérale, Hôpital Bobigny, Bobigny; 7 Département d'Oncologie Médicale, 8 Département d'Hématobiologie, 9 Département de Biochimie et de Biologie Moléculaire, Hôpital Avicenne, Bobigny; 10 Département d'Anatomopathologie, Centre Anticancéreux, Clermont-Ferrand, France
* Correspondence to: Dr J.-P. Spano, MD, Hôpital Pitié-Salpetrière, Département d'Oncologie Médicale, 47 Boulevard de l'Hôpital, 75013 Paris, France. Tel: +33-1-42-16-04-52; Fax: +33-1-42-16-04-65; Email: jean-philippe.spano{at}psl.ap-hop-paris.fr
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Abstract |
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Background: Epidermal growth factor receptor (EGFR) is overexpressed in many types of cancers, especially colorectal cancer (CRC), and seems to reflect more aggressive histological and clinical behaviors. The aim of this study was to evaluate EGFR immunohistochemical reactivity in CRC biopsies, and to analyze its relationship with various histological and clinical characteristics and survival.
Patients and methods: A composite EGFR score, obtained by multiplying the grade (% positive cells) by the intensity of labeling (0–9) was used to define patients with low or high EGFR expression whose clinicopathological features were then compared. Univariate tests and multivariate Cox proportional hazards model were applied for data analysis.
Results: Tissue sections from 150 CRC patients with a median follow-up of 40 months were examined. Median patient age at diagnosis was 70 years (range 38–89 years). EGFR reactivity was positive for 143 patients (97%) and high for 118 (80%). According to multivariate analysis, EGFR overexpression was significantly associated with tumor stage, with a higher percentage of EGFR overexpression in T3 than T4 (P=0.003) and not with overall survival.
Conclusions: EGFR was overexpressed in this CRC patient population and was significantly associated with TNM (tumor–node–metastasis) stage T3. In the context of a new therapeutic strategy using EGFR-targeted therapies, although EGFR remains a controversial prognostic factor, this expression–stage association may play a crucial role in a decision to initiate an adjuvant treatment.
Key words: colorectal carcinoma, EGFR expression, TNM, therapeutic strategy
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Introduction |
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Colorectal malignancies remain one of the leading causes of cancer deaths, worldwide, in men and women [1
]. Earlier diagnosis of colorectal cancer (CRC), better knowledge of its clinicohistological prognostic factors and its surgical treatment combined or not with chemotherapy or radiation therapy have contributed to the improved outcome of affected patients. The most significant and independent prognostic factors accepted to date in CRC remain the TNM (tumor–node–metastasis) stage and ‘potential’ residual disease after initial surgery [2]. Several other factors possibly independent for survival have been identified, but only a few of them have been shown to have an impact on CRC patients' prognosis and survival: obstruction or perforation, tumor grade, venous invasion, perineural invasion, age, gender or allelic loss of chromosome 18q [3]. In fact, some prognostic factors remain unknown. Although TNM classification is useful for staging patients and selects them for specific treatment, this classification is not sufficient as many patients at the same stage may have various outcomes. Hence, additional prognostic biomarkers are really needed for the management of CRC patients.
More recently, the epidermal growth factor receptor (EGFR) has been detected in a wide variety of cancers and, for some of them, its overexpression has been suggested as a factor of poor prognosis, associated with a more aggressive clinical progression, as in lung, breast, ovarian, bladder, oesophageal, cervical and head and neck cancers [4–10]. Epidermal growth factor receptor (EGFR) is a 170-kDa transmembrane glycoprotein composed of an intracellular tyrosine-kinase domain, a transmembrane lipophilic segment and an extracellular ligand binding domain, whose main autocrine ligands are epidermal growth factor (EGF) and transforming growth factor-alpha, described 20 years ago [11, 12]. EGFR belongs to a family of receptors known as the EGFR family, or ErbB tyrosine-kinase receptors, which comprises four proteins encoded by the c-erb B proto-oncogene: EGFR itself or ErbB1, ErbB2 or HER2/neu, ErbB3 or HER3 and ErbB4 or HER4 [13, 14]. It has been shown already that EGFR mRNA in culture human colorectal carcinoma cells may play a significant role during tumor progression [15] and EGF and EGFR levels have been shown to be higher in malignant zones of colorectal cancer specimens than in the surrounding mucosa [16]. In a clinical study, EGFR expression has been demonstrated to be associated with poor outcome in CRC patients with stage IV [17]. EGFR expression has also been reported to be associated with poor response rates in patients with locally advanced rectal cancer treated by radiation therapy [18]. Nevertheless, the presence of EGFR in CRC may also justify the application of specific EGFR targeted therapy in this cancer localization [19].
This context prompted us to evaluate EGFR expression in a standard population of CRCs and to analyze its relationship with the main clinicohistological prognostic factors and their respective impacts on patient prognosis and survival that could define new therapeutic approaches for patients with CRC.
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Patients and methods |
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Patients
One hundred and fifty paraffin-embedded tumor samples were available from 150 consecutive patients diagnosed in our hospital with CRC between 1996 and 2001. We excluded two patients who had only simple biopsies due to loco-regional extension, two others lost to follow-up and 14 whose follow-up was <1 year were not considered for the survival analysis. Finally, 148 patients were evaluated for the clinical and histological study and 132 patients for the survival analysis. Clinical examination, liver ultrasonography (US) or computed tomography (CT) scan and carcinoembryonic antigen (CEA) measurement were performed for each patient since their diagnosis, every 3 months for the first 2 years, every 6 months until the 5th year and annually thereafter, as well as a thoracic X-ray or CT scan every year.
Histology
All resected CRCs were received fresh, fixed in 10% pH-neutral formalin, embedded in paraffin. All patients had adenocarcinomas and were staged according to the International Union Against Cancer TNM staging (UICC/TNM) system [20]. Characteristics studied included age, sex, tumor site, tumor size, degree of histological differentiation (well/moderate/poor), number of invaded lymph nodes counted during the slide review and classified as N1 or N2, based on UICC/TNM staging system, perineural invasion and/or venous emboli (classified as present or absent), the presence of synchronous metastases and the occurrence of metastases during the follow-up period.
All histological slides were reviewed by two pathologists from our institution to confirm the diagnoses, and evaluate the patterns and intensity of EGFR reactivity.
Immunohistochemistry
Immunohistochemistry was performed using the avidin–biotin complex technique (Dako LSAB2 System, Peroxidase K675, Dako, Carpinteria, CA). Briefly, 5 µm-thick sections were cut from formalin-fixed, paraffin-embedded tissue, deparaffinized and rehydrated. After blocking endogenous peroxidase activity by immersion in 0.3% hydrogen peroxide in methanol for 30 min, antigen retrieval was performed by immersing the sections in 0.01 M sodium citrate buffer (citric acid and sodium citrate, pH 6.0) for 40 min at 99°C in a water bath. Primary mouse monoclonal antibody (EGFR/113, Novocastra Laboratories Ltd, Newcastle, UK), diluted 1:20, was deposited on the tissue sections for 60 min, at room temperature, followed by biotin-labeled affinity isolated goat anti-mouse immunoglobulins and streptavidin-coupled horseradish peroxidase. Complexes were visualized (brown) with 3,3'-diaminobenzidine (Dako) and the slides were counterstained with Mayer's hematoxylin, dehydrated and mounted with Peramount.
Each run included, for each patient, non-immune mouse IgG used as the primary antibody for the negative controls and normal epidermis known to express EGFR served as the positive control.
Evaluation of EGFR label
All the slides were scored by two pathologists blinded for all patient characteristics but TN stage. No nuclear or nucleolar reactivity was observed. Slides were assessed using a light microscope. In the case of differing opinions, the definitive assessment was obtained by consensus. The percentage of labeled cells was graded as follows: grade 0, no positive cells; grade 1, 1–25% labeled tumor cells; grade 2, 25–50% labeled tumor cells; grade 3, >50% positive tumor cells. The intensity of peroxidase deposits, ranging from light beige to dark brown, was assessed visually as indicating the tumor cell membrane, cytoplasm or both and was scored as 0 (negative), 1 (weak), 2 (moderate) or 3 (strong). A composite score, potentially ranging from 0 to 9, was obtained by multiplying the grade by the intensity [17]. Patients were analyzed as a function of their EGFR expression: low, <6 and high, 
6.
Statistical analyses
All statistical analyses were performed using Statistica, version 5.1. The chi-square test was used to compare the major clinicohistological prognostic factors for CRC as a function of the composite EGFR expression score (<6 or 6) obtained for these adenocarcinomas. Various typical prognostic factors were considered for univariate analysis (Table 1). Multivariate analysis, conducted with a backward stepwise application of Cox regression [21], was used to evaluate the influence of the selected prognostic factors on survival. Survival was calculated from the date of surgery. The effect of EGFR expression on survival was assessed using the Kaplan–Meier [22] method and compared using the log-rank test [23]. The significance level was defined as P
0.05.
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Results |
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Patient characteristics
Clinical and histological characteristics of the 148 patients are reported in Table 1. Most of the adenocarcinomas (43%) were located in the sigmoid colon. The majority (67%) were well differentiated, and the degree of differentiation could not be determined for five (3%). Among the 33 patients (22%) with metastases at the time of diagnosis, 29 had liver metastases and four had lung metastases. Seventy-two patients received chemotherapy according to their stage III or IV during the referred range of years, 1996–2001. The adjuvant chemotherapy for CRC patients with stage III in our institution was a 5-fluorouracil (5FU)/leucovorin-based regimen. However, not all patients with stage III rectal cancer received adjuvant chemotherapy, but received adjuvant or neoadjuvant radiotherapy. In metastatic CRC, patients received either 5FU with leucovorin in combination with irinotecan or with oxaliplatin. However, no patients received a new therapeutic strategy as EGFR-targeted therapy.
EGFR expression in CRCs
EGFR expression was detected in 143 (97%) of 148 assessable tumors. According to the labeling-intensity scores, 82 (55%), 47 (32%) and 14 (10%) adenocarcinomas were accorded scores of 3, 2 and 1, respectively. According to the EGFR-positivity grade, five (3%) adenocarcinomas had no reactivity, two (1%) had <10% positive cells, 20 (14%) had 10–50% reactive cells and 121 (82%) had >50% labeled cells. Examples of the different patterns of EGFR labeling are shown in Figure 1(A–. The composite scores, the product of positivity grade multiplied by labeling-intensity score for each patient, are shown in Table 2. EGFR expression was considered high (6) for 118 (80%) patients and low (<6) for 30 patients.
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In univariate analysis, the relationship between EGFR and clinicohistological features is shown in Table 3. EGFR overexpression was associated with tumor stage. The percentage of patients with EGFR overexpression was higher in TNM stage T3 than stage T4 CRCs (85% versus 59%, respectively, P=0.006). No relationship was found between EGFR expression and other clinicopathological variables studied (P>0.05).
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In multivariate analysis, logistic regression retained a significant association between EGFR overexpression and tumor stage (P=0.003), with the percentage of patients whose tumors overexpressed EGFR being four-fold higher in TNM stage T3 than TNM stage T4 (relative risk = 0.25; 95% confidence interval, 10–0.61).
Univariate prognostic analyses
With a median follow-up of 40 months (range 12–84 months), among 132 assessable patients with a follow-up >1 year, 84 patients were still alive and 48 patients were known to have died. The median overall survival for all patients was 61.7 months. Causes of death included disease progression (n=31), sepsis secondary to chemotherapy (n=7), secondary malignancy (n=1), cardiovascular disease (n=3), postoperative complications (n=2) and unknown cause (n=4). Nineteen patients suffered disease recurrence (five local and 14 distant metastases) and 10 developed a secondary malignancy during follow-up. The most common site of metastasis was the liver (n=9; 69%), followed by the lung (n=3; 23%).
The different variables analyzed by univariate analysis are shown in Table 4. Vascular emboli, perineural invasion, tumor stage, lymph-node involvement, tumor site, tumor differentiation status, synchronous metastases and CEA level were significantly associated with overall survival and thus appear to be prognostic for CRC outcome. Regardless of its composite score, EGFR expression was not an independent prognostic factor for specific and overall survival.
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Analysis of the impact of low or high EGFR-expression composite score on overall survival is shown in Figure 2. In addition, the analysis of the impact of low or high EGFR-expression composite score on overall and specific survival for the specific T3N0M0 stage group of CRC patients has shown no statistical difference between the two groups (P=0.97 and P=0.31, respectively).
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Multivariate analysis and logistic regression
According to our multivariate analysis (Cox model), using all the clinicohistological variables listed above and EGFR-expression composite score (<6 or
6), synchronous metastases (P=0.048) and venous emboli (P=0.018) remained significantly associated with overall survival. TNM tumor stage T4 at diagnosis (P=0.03) and synchronous metastases (P=0.001) were independently associated with specific survival. In multivariate analysis, EGFR was not an independent prognostic variable for both overall and specific survival. |
Discussion |
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This study was performed to evaluate retrospectively EGFR immunohistochemical reactivity in CRC patients and to explore the relationship between the extent of its expression and histological and clinical characteristics that may have an impact for patients' therapeutic strategies. We used an EGFR immunohistochemistry composite score (positivity multiplied by intensity), previously used in one of the largest studies on CRC evaluating EGFR expression [17
]. We found in our study that 143 tumors expressed EGFR and 118 (80%) overexpressed (6) the protein. When included along with known clinicopathological prognostic factors, we have shown a significant association between EGFR overexpression and tumor stage (P=0.003). Nevertheless, we failed to demonstrate EGFR as an independent prognostic variable. However, despite the fact that EGFR is not considered as a major prognostic factor to suggest a chemotherapy as adjuvant treatment for CRC patients, its major overexpression in stage T3 disease suggests the potential implication of EGFR-targeted therapies in such a setting.
EGFR has been found to be elevated in CRCs, with expression rates ranging from 25 to 77% [16, 17, 24]. This heterogeneity of expression is attributed to the different detection techniques, although most are based on quantitative immunohistochemical labeling with monoclonal antibodies [17]. Despite these known reproducibility and validation difficulties [14, 25, 26], immunohistochemical testing remains one of the most common methods used to assess EGFR expression and has also largely been validated for the screening of HER2 receptor [27].
To evaluate overexpression of EGFR in our study, we used the same EGFR composite score as that described by Goldstein and Armin [17], which seems to be one of the most promising and accurate scoring systems currently defined. Our observations confirm EGFR expression in colorectal adenocarcinomas [14, 16, 17, 28–31], consistent with high EGFR expression in 80% of the tumors examined.
Consistent with the results of the main studies [17, 29], we found no differences in EGFR expression among the different tumor sites. Only one study has demonstrated higher EGFR expression in cancers of the distal colon than the rectum [32].
Possible associations between expression (and overexpression) of EGFR and other clinicohistological parameters in CRC patients remain unclear. EGFR expression was reported to be correlated with more aggressive disease [33], increased risk of metastases [24], advanced tumor stage [34], significantly more reactivity in more deeply invaded regions compared with the superficial tumors [17] and higher rates of mesenteric lymph-node involvement [31].
According to the major studies published to date [14, 17, 25, 35], we found no significant association between histological grade and EGFR expression. Few studies reported a relationship between histological grade and EGFR overexpression [35–37]. However, in these studies, moderately and poorly differentiated tumors predominated, whereas our analysis was based on mostly (67%) well-differentiated adenocarcinomas.
Our most relevant findings demonstrate a significant association between high EGFR expression and TNM tumor stage at diagnosis, highlighting a relationship between EGFR overexpression and tumor invasion. This is the largest study to show that EGFR expression is significantly overexpressed in TNM tumor stage T3. This finding is in agreement with an earlier study examining fewer adenocarcinomas [31] and confirms the results of Goldstein and Armin [17], who demonstrated that EGFR immunoreactivity was significantly higher in the deepest regions of the tumors, as compared to the superficial or luminal zones.
Previous studies did not demonstrate any influence of EGFR expression on patient survival and disease-free survival [28, 29, 35, 38, 39]. Nevertheless, patients with EGFR overexpression seem to have a higher risk of generating liver metastases [24]. We did not find EGFR overexpression to be associated with a poorer prognosis or shorter overall survival.
Although EGFR in the overall population is not considered as a prognostic factor in CRC, it plays an important role in tumor cell proliferation [15], and consequently its overexpression in stage II disease (a situation in which chemotherapy is not a standard) represents a window of opportunity to test the efficacy of EGFR inhibitors in this specific patient population [7, 40]. Some preclinical and clinical studies [41, 42] have already demonstrated the efficacy of EGFR inhibitors in advanced colorectal carcinomas and their potential synergistic effects with chemotherapy and radiation therapy [43, 44]. This new finding should logically encourage researchers to continue their investigations in an adjuvant setting. In this context, EGFR expression has still not proven its predictive value; more effort needs to be targeted at improving simple EGFR detection techniques, such as examining the downstream signaling pathway and EGFR somatic mutations [45].
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Notes |
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These two authors contributed equally to this study 
Received for publication February 27, 2004. Revision received July 23, 2004. Accepted for publication July 26, 2004.
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