Annals of Oncology Advance Access originally published online on April 20, 2006
Annals of Oncology 2006 17(6):945-951; doi:10.1093/annonc/mdl053
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© 2006 European Society for Medical Oncology
Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer
1 Department of Medicine and Translational Research Unit UPRES03535, Institut Gustave Roussy, Villejuif, France; 2 Unité d'Oncologie Médicale, Pitie Salpetriere Hospital, Paris, France; 3 Immunology Unit, INSERM U543, Hopital Pitie-Salpetriere, Paris, France; 4 Departments of Pathology, Breast Medical Oncology, Biostatistics and Cancer Biology, MD Anderson Cancer Center, Houston, Texas, USA
* Correspondence to: Dr F. Andre, Breast Cancer Unit, Institut Gustave Roussy, 39 rue C. Desmoulins, 94805 Villejuif, France. Tel: +33-142114371; Fax: +33-142115274; E-mail: fandre{at}igr.fr
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Abstract |
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Background: Recent studies have suggested that chemokine receptors are involved in development of organ-specific pattern of metastases. In the present study, we evaluated the association between the chemokine receptors expressed in primary tumor cells and the site of metastatic relapse in patients with breast cancer.
Methods: Primary tumors were obtained from 142 patients with axillary node–positive breast cancer and stained for CX3CR1, CXCR4, CCR6, and CCR7 expression. All statistical analyses were adjusted for systemic post-operative treatment.
Results: After a median follow-up of 13 years, none of the chemokine receptors was associated with overall survival or disease free survival. However, expression of chemokine receptors was found to be associated with increased risk of relapse in certain organs. By estimating the Mantel-Haenszel odds ratios (OR), CXCR4 was associated with increased risk of metastasis to the liver (OR = 3.71, P = 0.005), CX3CR1 was associated with metastasis to the brain (OR = 13.18, P = 0.01). Patients with CCR6 positivity were more likely to develop a first metastasis in the pleura (OR = 2.82, P = 0.06). In addition, CCR7 expression was associated with the occurrence of skin metastases (11% versus 0%, P = 0.017).
Interpretation: Expression of chemokine receptors in the primary tumor predicts the site of metastatic relapse in patients with axillary node positive breast cancer. This study, in concordance with the data obtained in animal models, suggests that the chemokine receptors family could be the biological support of the ‘seed and soil’ theory.
Key words: breast cancer, chemokine receptors, metastases
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Occult dissemination of tumor cells is the main cause of recurrent metastatic disease in patients with breast cancer who have undergone resection of their primary tumor. Adjuvant systemic chemotherapy and endocrine therapies have been shown to reduce the risk of recurrence and deaths in women with primary breast cancer (PBC), implying that occult micrometastases are present at the time of diagnosis. The formation of metastatic colonies is not a random process and it is believed that it started early during the growth of the primary tumor, probably increasing with time. The peculiar distribution of metastasis in the various cancers was recognized first in 1889 by Paget [1
] and called ‘seed and soil’, essentially indicating that different organs provide growth conditions optimized for specific cancers. Although this clinical phenomenon was extremely well described, the underlying biological factors remain to be determined.
Circulating leukocytes and stem cells use chemo-attractants called chemokines for homing to specific organs [2]. Chemokines are molecules that are structurally and functionally similar to growth factors. They bind to G-protein-coupled receptors on leukocytes and stem cells; the receptors are so-called because they work through guanine-nucleotide-binding (G) proteins to spark off intracellular signaling cascades that prompt migration towards the chemokine source. Recent studies have shown that a leukocyte chemo-attractant receptor named CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 7 (CCR7), are consistently expressed in breast cancer cells [3]. Interestingly, the matched chemokines are known to be expressed in sites frequently involved with breast cancer metastases. For instance, CXC chemokine ligand 12 (CXCL12, also known as stromal-cell–derived factor 1-alpha, or SDF-1
), the chemokine recognized by CXCR4, is expressed in lung, liver and brain [4]. Studies performed in animal models have shown that both CXCR4 and CCR7 are involved in the homing of cancer cell further suggesting that the expression of CXCR4 and CCR7 could play a role in the metastatic phenomenon [3, 6]. Furthermore, it has been suggested that other chemokine receptors, could potentially contribute to the process of homing of cancer cells. CCR6, is a chemokine receptor that is highly expressed in CD34+ cell-derived dendritic cells (DC), but not in monocyte-derived DCs, and its ligand is a recently described CC chemokine, macrophage inflammatory protein (MIP)-3 [7]. CX3CR1 is the receptor of fraktalkine, which mediates chemo-attraction of macrophages and natural killer cells [8]. CCR6, CCR7 and CX3CR1 have been reported to be expressed in other malignancies including pancreatic, gastric, prostate and non-small cell lung cancer (NSCLC) [7–10].
In the present study, we evaluated the expression of CXCR4, CX3CR1, CCR6 and CCR7 in a series of 142 patients with axillary node-positive PBC who did not receive adjuvant chemotherapy. We tested the hypothesis whether the expressions of these chemokine receptors could specifically predict the site of recurrence at any time during follow-up of the disease. Furthermore, we investigated the association of chemokine receptors and long-term outcome.
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patients and methods |
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study population
Surgical specimens were collected between 1972 and 1979 from 142 patients with resectable breast cancers treated at The Institut Gustave Roussy, Villejuif, France. All patients presented with an axillary node-positive disease without metastases at the time of diagnosis, and were included in a prospective randomized trial that compared the post-operative administration of double stranded RNA with placebo [11
]. Local treatment consisted of a mastectomy plus axillary node dissection followed by a complementary local radiotherapy. None of the patients received adjuvant chemotherapy. The study was approved by the institutional review board committee at The Institut Gustave Roussy, Villejuif, France. All clinical and pathological data including demographics, pathologic tumor size and lymph node status were obtained from medical records. Data regarding site of recurrences, time of recurrences and death from any cause were also collected from medical records. Tumors were fixed in Bouin liquid.
immunohistochemical staining for chemokine receptors
A tissue array of paraffin-embedded tumor specimens was constructed from archived tissue samples of surgically resected breast cancers. Sections were incubated with anti-HER2-neu (NCB11 antibody), anti-CX3CR1 (AB1891, Chemicon International), anti-CXCR4 (44176.111, IgG2b, R&D Systems, Minneapolis, MN; 1:150 dilution), CCR6 (clone 53103–111, R&D system, Minneapolis, USA), and CCR7 (clone 2H4, Pharmingen, San Diego, USA) antibodies, as recommended by manufacturer or suppliers. Each section was read by two pathologists blinded for clinical data. The staining was determined semi-quantitatively according to the intensity (0 = no staining, 1 = weak staining, 2 = moderate staining, 3 = strong staining). Only cytoplasmic pattern was considered as positive. At the beginning of the study, it was decided that staining would be considered positive when a strong cytoplasmic staining was observed as previously reported [14]. CXCR4, CCR7 and CX3CR1 stainings were therefore considered positive when the staining was coated 3. Since only a few tumors (n = 8) presented a strong staining for CCR6, it was retrospectively decided that CCR6 staining was positive when the score was 
1. HER2-neu was considered as positive when more than 10% of the tumor cells showed a complete membrane staining by immunohistochemistry. The expression of estrogen receptor was assessed retrospectively by immunohistochemistry (clone 6F11, Novocastra) in 106 patients and at the time of diagnosis by biochemistry in 23 patients. Tumor was considered positive when more than 10% tumor cells were stained or if there was more than 100 fmol of receptor per g of tissue.
statistical analysis
Statistical analyses were carried out with S-Plus 6.1 (Seattle, WA) and SAS 8.02 (Cary, NC). The analyses included the associations between different chemokine receptors and outcomes such overall survival, metastasis-free survival, the first site of metastasis, and site of metastasis at any time during follow-up adjusted for treatment with double stranded RNA. Chi-square or Fisher's exact tests were used as appropriate to test for associations between chemokine receptors and other patient characteristics. Overall survival was measured from the date of diagnosis to the date of death. Metastasis-free survival was measured from the date of diagnosis to the date of first metastasis at any site. The Kaplan–Meier method was used to estimate overall survival and metastasis-free survival among all patients and for each treatment group, and the log rank statistic was used to test for differences between groups. Metastatic sites that were analysed included bone, lung, skin, pleura, liver, and lymph nodes. Patients who had their first metastasis at a different site were considered censored at that date and patients who died before developing metastasis were considered censored at the date of death.
The associations between receptor expression and each time-to-event outcome were estimated with Cox proportional hazards models that included terms for the receptor and treatment group. Finally, while sites of relapse were recorded throughout the follow-up period; the date each metastasis was not available. Therefore, in order to explore the relationship between chemokine receptor expression and site of metastasis as recorded at any time during follow-up, the Mantel-Haenszel test was used to check for an association between receptor expression and site of metastasis after adjustment for treatment with double stranded RNA. The association between each chemokine receptor expression and the occurrence of site-specific metastases was also determined by a multivariate analysis. For this analysis, each site of metastasis was considered independent of time, or as recorded at any time during follow-up, with logistic regression models that included a single chemokine receptor and patient clinical characteristics (including treatment with double stranded RNA, ER status, tumor size, tumor grade, number of positive nodes, and Her2 status). Because the number of events varied by outcomes, all clinical characteristics could not always be reliably modeled. The best fitting model was selected in each case. For all the analyses, a P value 
0.05 was considered statistically significant. It is of note that each site of metastasis was taken into account for the analysis when a patient presented metastases in multiple organs.
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Patient and tumor characteristics
One hundred and forty-two patients were included in the present study. Patient characteristics were shown in Table 1. Briefly, the median age was 50 years (range 29–64). The median number of axillary nodes involved was 4 (range 1–32) and the median pathologic tumor size was 25 mm (range 10–90 mm). Forty-nine patients (35%) had a poorly differentiated tumor (grade = 3). Seventy-seven (60%) out of 129 assessable tumors expressed estrogen receptor. Seventy-two patients (51%) were randomized to receive adjuvant treatment with double stranded RNA (polyAU). As previously stated [11
], no patient received adjuvant chemotherapy, nor tamoxifen. Twenty patients (13%) who were menstruating, aged below 50 and whose tumour expressed estrogen receptor received a pelvic radiotherapy.
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Cytoplasmic immunostaining was regarded as positive for chemokine receptors as reported previously [14
] (Figure 1). Positivity rates observed for the various chemokine receptors were as follows: CX3CR1, 44%; CXCR4, 31%; CCR7, 67%; and CCR6, 36% (Table 1). The concomitant expression of the four chemokine receptors was assessable in 105 patients. Twenty-nine (28%), 49 (47%), 8 (8%) and 11 (10%) tumors expressed one, two, three or the four chemokine receptors respectively. Eight tumors (8%) did not express any chemokine receptor. Expression of any chemokine receptor did not correlate significantly with any clinicopathologic characteristics (Table 1) including HER2-neu expression in the primary tumor (HER2-neu 3+ in CXCR4-positive versus negative: 3 of 13 versus 39 of 119, respectively, P = 0.550).
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associations of biomarker expressions with clinical outcome
The median follow-up was 13 years (range 0.3–27.7). Seventy-five patients (53%) were found to have a metastatic relapse. Eighty-seven patients died (62%) and the estimate of overall survival at 10 years among all patients was 57% [95% Confidence Interval (CI) = 49.5%, 65.8%]. Post-operative administration of polyAU did not improve OS (P = 0.16), nor the disease-free survival (P = 0.33). The expression of CX3CR1, CXCR4, CCR7 or CCR6 was not associated with significant statistical differences in overall survival or disease free survival (Table 2). There was no correlation between the number of chemokine receptor expressed and the occurrence of metastases. Seven (87%), 16 (55%), 27 (55%), 4 (50%) and 7 (64%) patients presenting tumor that expressed no, one, two, three or four chemokine receptors have presented a metastatic relapse respectively.
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associations of biomarker expression with the occurrence of site of metastases
The distribution of metastatic sites is reported in Table 3. Twenty-seven out of the 75 patients (36%) with metastatic relapse have presented metastases in multiple sites. The expression of chemokine receptors by tumor cells predicted the occurrence of metastasis in a specific organ during the natural progression of the disease. Table 4 shows the odds ratios from the Mantel-Haenszel test for each receptor and each site of metastasis. The Mantel-Haenszel odds ratio is a common overall odds ratio for both of the treatment groups. After adjusting for treatment with polyAU, CXCR4 was significantly associated with metastasis to the liver (P = 0.005), CX3CR1 was significantly associated with metastasis to the brain (P = 0.01) and HER2-neu was also significantly associated with metastasis to the liver (P = 0.01). There was some evidence of association between other receptors and sites of metastasis although the 0.05 threshold was not reached. These include the association of CCR6 with pleura, CXCR4 with the lung, and HER2-neu with the brain. The expression of chemokine receptors did not predict for the occurrence of bone metastases in our series. Since the Mantel–Haenszel test could not be used to test the association between CCR7 expression and the occurrence of skin metastases, we compared the incidence of skin metastases in patients with CCR7– and CCR7+ tumors. None of the 44 patients with CCR7– tumor has presented skin metastases, compared with 11 out of 93 patients with CCR7+ tumors (P = 0.017,
2 test).
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Table 5 shows the results of the multivariable models of the sites of metastasis. After adjustment for clinical characteristics, CCR6 remained significantly associated with metastasis in the pleura (odds ratio (OR) = 4.22, P = 0.02), CXCR4 in the cytoplasm remained significantly associated with metastasis in the liver (OR = 4.18, P = 0.02), CX3CR1 remained significantly associated with metastasis in the brain (OR = 10.27, P = 0.047), and Her2 remained significantly associated with metastasis in the brain (OR = 10.11, P = 0.01). After adjustment for clinical characteristics, the odds ratio for metastasis to the lung associated with CXCR4 in the cytoplasm was 2.41 (P = 0.10), and the odds ratio for metastasis to the liver associated with Her2 was 3.51 (P = 0.09). This multivariate analysis did not explore the correlation between CCR7 and the occurrence of skin metastases.
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discussion |
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The present study demonstrates that multiple chemokine receptors are expressed in a significant proportion of primary breast cancers and can predict for the site of recurrence. For instance, CXCR4 predicted for the development of liver metastases. It is noteworthy that only primary tumor samples of patients with axillary node positive disease who have potentially a high risk for metastatic relapse, and did not receive adjuvant chemotherapy, were included in the current study since our main goal was to investigate the association of chemokine receptor expression with the site of metastatic relapse and outcome. These data have significant implications and first suggest that chemokine receptor family could contribute to support the ‘seed and soil’ phenomenon. Therefore, it calls into question if the expression of chemokine receptors already in the primary tumor can indicate an active and functional role of chemokines in the metastatic process. This will require the concomitant expression of the chemokine receptor-ligand complex at the site of metastasis (e.g. the interaction of SDF1-
and CXCR4 in the target organ).
The expression of CXCR4 by cancer cells has already been extensively reported [2, 12, 13, 14]. A recent study has suggested that this expression could be regulated by HER2-neu [13]. However, this remains a controversial issue and in the current study we were not able to confirm a correlation between HER2-neu and CXCR4 overexpression in primary breast cancer in concordance with the study of Cabioglu et al. [12]. CCR7 has also been reported to be expressed in various cancers including breast, NSCLC, gastric and esophageal in which settings demonstrated associated with higher rate of lymph node involvement [3, 5, 9, 10, 15]. CX3CR1 and CCR6 have been described to be expressed by prostate cancer cells and pancreatic cancer cells, respectively. We report here that all of these chemokine receptors were also expressed in primary breast cancer. These data are concordant with those reported in previous studies for CXCR4 and CCR7, and confirm data reported in other tumor models for CCR6 and CX3CR1.
Chemokines are known to mediate chemo-attraction of leucocytes to specific organs. SDF1- (CXCL12), the CXCR4 ligand has been reported to be expressed both in liver and lung [2]. An association of CXCR4 expression with lung and liver metastases has been shown in various cancers including breast and colon cancer and malignant melanoma [2, 3, 16, 17]. Furthermore, lung metastasis of breast cancer cells in immunodeficient mice could be inhibited by a neutralizing antibody against CXCR4 or the growth of the lung metastasis could be delayed by inhibiting CXCR4 with RNAi, or the specific CXCR4-antagonist AMD3100 [3, 18, 19]. Our study is concordant with these data since we show that CXCR4 expression predicted a metastatic relapse in liver and lung and was further associated with a significant increased risk for shorter metastasis free survival to liver as the first metastatic site. These interesting data suggest the intriguing possibility of using CXCR4 inhibitors to prevent the visceral metastases in high-risk PBC. Moreover, SDF-1 has also shown to be a proliferative and chemotactic factor particularly for estrogen-receptor positive breast cancer [20]. In these cancers, antiestrogens have demonstrated the ability to decrease basal levels of SDF-1 suggesting the intriguing possibility that the benefit of hormonal treatments could potentially be partially explained through this mechanism.
The Fractalkine (CX3CL1) has been previously reported to be expressed by astrocytes and to mediate neuronal plasticity [21]. Our results confirm the possible implication of fractalkine in the homing of tumor cells to brain since the expression of CX3CR1 in tumor cells predicted the occurrence of brain metastases. MIP3, the ligand for CCR6, is known to be released by macrophages in inflammatory sites [22]. CCR6 expression has been demonstrated to play a role in pancreatic cancer progression [23]. CCR6 was also found to be overexpressed in liver metastasis of ovarian, thyroid and colon cancer [24]. Because human liver constitutively expresses CCL20, it could attract CCR6 expressing cancer cells [25]. However, according to our knowledge, there is currently no data that reported the expression of MIP-3 in patients with pleural effusions. It is therefore not possible to assess whether the higher incidence of pleural metastases in patients whose tumor overexpress CCR6 could be related to MIP3 overexpression in pleura.
The other chemokine receptor in our panel, CCR7, is usually reported to mediate the homing of memory T cell and mature dendritic cells to the lymph nodes. Some studies have suggested that CCR7 is also an essential mediator for entry of dendritic cells into the lymphatic vessels [2, 26]. An increased expression of CCR7 has also been shown in primary tumors of patients with lung cancer [26], esophageal [27], and gastric carcinoma [28] with lymph node metastases. These data suggested a biological role of CCR7 expression in the development of lymphatic metastases in different cancer types [25–28, 29]. Wiley et al. [29] reported that injection of CCR7-transfected B16 melanoma cells into mice increased the detection of tumor cell metastases to draining lymph nodes. Furthermore, Muller et al. [3] showed increased chemotaxis and chemoinvasion of breast cancer cells towards CCL21, the ligand for CCR7, gradients indicating that CCR7/CCL21 interactions may also play a role in breast cancer metastases to lymph nodes. In concordance with these observations and previous studies in other cancer types, we have previously shown that high cytoplasmic CCR7 expression in T1 breast cancers was associated with lymph node metastases [12]. In the present study, CCR7 expression was found to be associated with a higher rate of skin relapses. Since some studies have suggested that CCR7 is an essential mediator for entry of dendritic cells into the lymphatic vessels including dermal vessels, we hypothesize that the high incidence of skin metastases observed in patients whose tumors overexpress CCR7 could be explained by a CCR7-mediated transfer of tumor cells from the primary tumor to dermic lymphatic vessels. This hypothesis is under exploration in mice models.
In this study HER2-neu expression was found to be a poor prognostic factor in this population of node-positive breast cancer patients. This data support the appropriate use of this type of retrospective studies for the identification of molecular markers that could contribute to the development of more effective and tailored adjuvant treatments (e.g. trastuzumab in HER-2 overexpressing or amplified breast cancer) [30]. The results of this study clearly indicates that the complex network of chemokines and the corresponding cellular receptors are key players in the establishment of a non-random metastatic process, further emphasizing the role of the micro-environment. These data suggest that in the future, with the increasing knowledge of the biological factors involved in the trafficking of cancer cells, our current approach to definition of risk of recurrence will be refined to include, for example, traditional factors represented by lymph nodes metastasis and age, also the expression of chemokine receptors. The immediate implications of this data is that the identification of women at high-risk of developing visceral metastasis (e.g. CXCR4 expression) [31] can support the investigation of the possible antimetastatic role of CXCR4 inhibitors. These agents could provide the opportunity to reduce the incidence of more life-threatening metastatic disease hence contributing to an overall improvement in prognosis of these patients.
In conclusion, our data suggest that the pattern of chemokine receptors expressed by primary breast cancer determines the site of metastatic relapse. This data therefore suggests, as previously reported in animal models, that the chemokine receptor family could be the biological support of the ‘seed and soil’ phenomenon. If confirmed, these findings could have important clinical implications regarding the treatment and follow-up of patients with primary breast cancer.
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Notes |
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FA, NC, HA and JCS, MC equally contributed to this work. 
Received for publication October 14, 2005. Revision received February 15, 2006. Accepted for publication February 16, 2006.
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