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Originally published as JCO Early Release 10.1200/JCO.2005.04.8587 on July 5 2006 © 2006 American Society of Clinical Oncology.
FGFR4 Arg388 Allele Is Associated With Resistance to Adjuvant Therapy in Primary Breast Cancer
From the Department of Obstetrics and Gynecology, Institute of Pathology, and Institute for Medical Statistics and Epidemiology, Technical University of Munich, Munich; and the Department of Molecular Biology, Max-Planck-Institute of Biochemistry and U3 Pharma AG, Martinsried, Germany Address reprint requests to Nadia Harbeck, MD, Department of Obstetrics and Gynecology, Technical University of Munich, Ismaninger Strasse 22, D-81675 Munich, Germany; e-mail: nadia.harbeck{at}lrz.tum.de
Purpose A recent study presented first evidence that a single nucleotide polymorphism (SNP) at codon 388 of fibroblast growth factor receptor 4 (FGFR4) gene, causing a transmembrane domain missense mutation (Gly388Arg), is associated with disease outcome in node-positive breast cancer. This article addresses the clinical relevance of this SNP, FGFR4 genotype, phenotype, and HER2 regarding patient outcome and influence of adjuvant systemic therapy in a substantial primary breast cancer collective (n = 372; median follow-up, 94.5 months). Methods Polymerase chain reaction restriction fragment length polymorphism analysis of germ-line polymorphism was performed in uninvolved lymph nodes; FGFR4 and HER2 expression were assessed immunohistochemically in tissue microarrays. Results In 51% of patients, homo- or heterozygous Arg388 allele was present. No correlation existed between FGFR4 genotype and expression or HER2 status. In node-negative patients, FGFR4 genotype was not correlated with disease outcome. In node-positive patients, however, FGFR4 Arg388 was significantly associated with poor disease-free survival (DFS; P = .02) and overall survival (OS; P = .04). Notably, this association seems to be attributable to relatively poor therapy response in Arg388 carriers, reflected in their significantly shorter DFS (P = .02) and OS (P = .045) among patients receiving adjuvant systemic therapy. It is also seen as a significant interaction term in a multivariate proportional hazards model with Arg388 carriers having only about half as much benefit from adjuvant systemic therapy as wild-type carriers. Conclusion According to this study, FGFR4 Arg388 genotype is a marker for breast cancer progression in patients with adjuvant systemic therapy, particularly chemotherapy, and thus may indicate therapy resistance.
Uncontrolled cellular growth and metastasis are characteristics of malignant tumors. Metastasis requires tumor cells to detach from the primary tumor, cross tissue boundaries, enter and exit the circulatory system, and finally infiltrate distant organs.1 During tumorigenesis, those properties are acquired in a multistep process based on accumulation of innate and acquired genetic defects.2 The genes concerned usually play a decisive role in regulation of cell growth. Hence, protein tyrosine kinases, transducting growth-stimulating signals into cells, are often the decisive points where regulation fails.3 Alterations in receptor tyrosine kinase genes such as specific point mutations or gene amplification induce neoplastic disorders,4,5 as first demonstrated for HER2 oncogenic activation.6 The fibroblast growth factor receptor (FGFR) family with its four closely related human members is also one of the tyrosine kinase receptors. This family, comprising more than 20 known ligands, is critically involved in cell growth, differentiation, migration, angiogenesis, and tumorigenesis,7 and is linked to human diseases: Gly380Arg and Ala391Glu amino acid substitutions in the FGFR3 transmembrane domain cause achondroplasia and Crouzon syndrome.8,9 FGFR2 is required in limb and lung development10; its point mutations lead to Crouzon syndrome.11,12 FGFR3 and FGFR2 somatic mutations have been detected in human bladder, cervical, and colorectal carcinomas.13,14 FGFR1 and FGFR3 gene translocations play a role in development of leukemia and multiple myeloma.15,16 FGFR1 signaling is critical for prostate cancer cell growth.17FGFR4 is decisively involved in differentiation of limb muscles18 and, like FGFR1, it is highly expressed in mammary carcinomas.19,20 High FGFR4 expression was demonstrated in pancreatic21 and renal cell carcinoma.22 In 2002, Bange et al discovered a germ-line polymorphism in the gene encoding for FGFR4.23 The single nucleotide polymorphism (SNP) at codon 388, from G to A, results in a change of the amino acid sequence of the FGFR4 from glycine to arginine (Gly388 to Arg388). The result is a charged amino acid in the highly conserved and normally hydrophobic transmembrane region. Analysis of three geographically separated groups indicated that the germ-line polymorphism occurs in approximately 50% of the human population; FGFR4 Arg388 genotype is not involved in tumor initiation, since FGFR4 alleles are similarly distributed in breast cancer patients and controls. FGFR4 Arg388 was over-represented in node-positive breast cancer patients with early relapse but was not associated with shortened disease-free survival (DFS) in node-negative patients.23 HER2 status was significantly associated with FGFR4 Arg388.23 Recently, Streit et al24 demonstrated that high expression of the FGFR4 Arg388 allele was associated with poor clinical outcome in head and neck squamous cell carcinoma (HNSCC). An impact of Arg388 polymorphism on patient outcome was also reported in lung adenocarcinoma.25 These findings underline the clinical relevance of the FGFR4 Arg388 polymorphism in cancer. It remains an open question whether the observed impact is purely prognostic or involves differential response to therapy. Given the clearly documented impact of adjuvant therapy on DFS,26 primary breast cancer is particularly well suited for distinguishing purely prognostic from predictive impact. The present study was therefore intended to validate the relevance of FGFR4 Arg388 polymorphism in breast cancer in a substantially larger patient cohort with long follow-up and complete, representative adjuvant therapy. For the first time, FGFR4 expression and HER2 status by immunohistochemistry (IHC) are analyzed next to FGFR4 genotype in breast cancer—of interest in view of the previously reported association between HER2 and FGFR4 Arg388. We focus on the influence of adjuvant systemic therapy on prognostic impact of FGFR4, because follow-up results indicating impact on disease outcome may be confounded by differential therapy response.27
Patients and Tissue Samples Tissue specimens of 372 consecutive primary breast carcinomas were collected by the Pathology Department, Technical University of Munich (TUM; Munich, Germany), all patients diagnosed and treated at the TUM Department of Obstetrics and Gynecology (1987-2001); treatment decisions were based on consensus recommendations at the time. All patients gave informed consent for research use of tissue. After surgery (modified radical mastectomy or breast-conserving therapy), 73 patients, all of them node negative, received no adjuvant systemic therapy. One hundred fourteen patients received adjuvant chemotherapy, 87% cyclophosphamide/methotrexate/fluorouracil (CMF) -based regimens; 164 patients received tamoxifen, 10 patients combined chemoendocrine therapy (10 unknown). One patient had missing nodal status. Follow-up was performed regularly; median follow-up in patients still alive at analysis was 94.5 months (range, 7 to 199 months). Relapse data were available in 357 patients: 128 (36%) experienced disease recurrence; 81% (n = 104) distant relapses; and 140 (38%) death.
Sequence analysis of FGFR4
FGFR4 Semiquantitative IHC
FGFR4 Expression Analysis
HER2 Semiquantitative Immunohistochemistry
Statistical Methods
Distribution of FGFR4 Gly388Arg Polymorphism In the present primary breast cancer cohort, 156 patients (49%) were homozygous for Gly388 allele, with 136 heterozygous (43%) and 24 homozygous (8%) for Arg388, consistent with Hardy-Weinberg equilibrium for a Gly388 frequency of approximately 70%. This is consistent with previous reports23 of approximately 50% homo- or heterozygous carriers of the Arg388 allele in both the healthy population and in breast and colon cancer patients, independent of ethnic background. No significant association was found between clinical or histopathological tumor characteristics and FGFR4 genotype (Table 1). Borderline significant associations of Arg388 allele presence with higher grade (P = .056) and with larger tumors (P = .058) were seen.
Expression Patterns of FGFR4 and HER2 Seventy percent of invasive breast carcinoma tumors had low (1) to moderate (2), 22% strong (3), and 8% score 0 FGFR4 staining (Fig 1). FGFR4 staining (all scores) showed a diffuse and granular cytoplasmatic pattern; distinct membrane staining was observed in some tumors but never without cytoplasmatic staining. FGFR4 and HER2 scores were not significantly correlated. FGFR4 and HER2 IHC results are summarized in Table 2.
FGFR4 Genotype, Expression of FGFR4 and HER2 FGFR4 genotype showed no significant association with FGFR phenotype (IHC; Table 3); this holds between each genotype and each expression pattern separately or grouped (high/low) and for grouped FGFR4 genotype (wild-type [Gly/Gly] v homozygous or heterozygous Arg388 carriers). No significant correlation was seen between FGFR4 genotype and HER2 expression. Interestingly, no HER2 overexpression (ie, score 3+ or even 2+) was found in tumors with absent FGFR4 expression (ie, score 0; Table 2); absence of staining (score 0) in HER2 and in FGFR4 expression were significantly (P = .013) associated.
FGFR4 Genotype and Disease Progression Consistent with Bange et al,23 no significant association between FGFR4 genotype and disease progression or patient outcome was seen for the whole cohort (DFS, P = .13; overall survival [OS], P = .09) and for node-negative patients (DFS, P = .51; OS, P = .71). In node-positive patients, however, presence of Arg388 allele was associated with shorter DFS (P = .019) and OS (P = .04; Fig 2). No significant association was found between presence of Arg388 allele and DFS or OS in the small (n = 13) node-positive subgroup with no FGFR4 staining.
FGFR4 Genotype and Adjuvant Systemic Therapy The relationship between FGFR4 genotype and course of disease depended on administration of adjuvant systemic therapy: No significant survival differences between FGFR4 genotypes were found in patients without adjuvant systemic therapy. However, with adjuvant systemic therapy, the wild-type cohort showed better DFS (P = .025) and OS (P = .045; Fig 3). Separately considering adjuvant therapy types (chemo-/endocrine), no significant survival difference was seen in patients with adjuvant endocrine therapy (Fig 3). In contrast, in patients with adjuvant chemotherapy, significant survival differences were observed favoring FGFR4 wild-type carriers for DFS (P = .023) and OS (P = .08; Fig 3).
FGFR4 Arg388 Allele As a Predictor for Resistance to Systemic Therapy: Interaction Analysis These results strongly suggest the presence of an interaction. Multivariate analysis was performed in two steps: In the first step, the model included established prognostic factors (affected lymph nodes, tumor stage, hormone receptor status, grading, and age) as well as adjuvant chemotherapy and endocrine therapy; nodal involvement was coded as fractional rank of number of nodes; squared fractional rank was included. The step also included a binary variable FGFR4 genotype (wild-type [Gly/Gly] v homozygous or heterozygous Arg388 carriers). In the second step, interactions between this binary variable FGFR4 genotype and the following factors were included: presence of adjuvant therapy (either or both), chemotherapy, endocrine therapy, nodal status, and ranked nodal involvement (Table 4). The resulting model showed that, next to the hazard associated with lymph node involvement and the substantial benefit from both kinds of adjuvant systemic therapy, the interaction between FGFR4 genotype and adjuvant therapy had the strongest impact on DFS. Specifically, the interaction implies that patients with the Arg388 allele had only about half as much benefit from adjuvant systemic therapy as patients with the wild type (Table 4). No difference between heterozygous and homozygous Arg388 carriers was seen in this regard. An alternative interaction model including the interactions between each separate type of therapy (chemo- and endocrine) and FGFR4 genotype (but not adjuvant therapy as a whole) yields a significant interaction with chemotherapy (hazard ratio [HR] = 2.2; 95% CI, 1.1 to 4.4; P = .03) of similar impact (compare Kaplan-Meier analysis in Fig 3). In addition, neither an impact of FGFR4 expression nor an interaction of FGFR4 expression with therapy was found.
FGFR4 and HER2 Expression and Disease Progression No significant association between FGFR4 and HER2 expression was observed. There was no significant impact of FGFR4 expression or HER2 expression on disease outcome. Moreover, no significant correlation between HER2 status and disease outcome was observed.
To validate the role of FGFR4 Arg388 polymorphism in breast cancer as first reported by Bange et al,23 a substantially larger patient cohort with long-term follow-up has now been evaluated, including FGFR4 and HER2 expression as well as FGFR4 genotype. Associations between FGFR4 and disease outcome were analyzed, taking the influence of different adjuvant systemic therapies separately into account. The allele proportions for Gly388 and Arg388 found here resemble those reported by Bange et al23 in the normal population and in breast and colon cancer patients, independent of ethnic background, and these proportions are consistent with Hardy-Weinberg equilibrium for a Gly388 frequency of approximately 70%. No significant associations were found between FGFR4 genotype and established clinicopathological parameters, in accordance with Jezequel et al,29 although borderline significant associations of Arg388 allele presence with higher grade and with larger tumors were noted. We have now extended the focus, considering both FGFR4 genotype and phenotype. No significant correlation between FGFR4 genotype and FGFR4 expression was found, in accordance with Streit et al for HNSCC.24 Moreover, no significant association between FGFR4 expression and disease outcome or response to adjuvant therapy was observed. Thus far, FGFR4 genotype provides the clinically more relevant information. Plausible explanations include the following: Arg388 allele might not influence protein expression; or the scoring system might not adequately capture the underlying biology. In this larger cohort, no significant correlation between FGFR4 geno- or phenotype and HER2 expression was observed. Remarkably, no high HER2 expression (ie, 3+ or even 2+) was observed in those 16 patients scored 0 for FGFR4 expression. Influence of HER2 on disease course reflects a combination of both prognostic and predictive impact.30 Hence, the lack of significant correlation between HER2 status and disease course here could reflect masking of prognostic impact by predictive impact (therapy resistance/response), which sometimes becomes visible when stratifying according to nodal status.30 As previously reported,23 we observed a significant association between FGFR4 genotype and disease outcome in node-positive but not in node-negative patients; FGFR4 Gly388 was associated with favorable DFS and OS. These results support the hypothesis that Arg388 allele accelerates advanced breast cancer progression, as reported for colon23 and soft-tissue carcinomas.31 For HNSCC, this association was demonstrated for tumors with high FGFR4 expression.24 There is evidence that "prognostic" impact of a factor can be confounded by administration of adjuvant systemic therapy.27,32 Consequently, a factor’s influence on tumor aggressiveness is reflected in DFS in patients without adjuvant systemic therapy, whereas a factor’s predictive impact (therapy resistance or response) emerges in DFS of patients with adjuvant systemic therapy. Whereas adjuvant therapy tends to be homogeneous and guideline-oriented, OS results are confounded by individualized heterogeneous therapies following relapse. Because indication for adjuvant systemic therapy was linked to nodal status when our patients were treated, we thus analyzed impact of FGFR4 genotype on survival considering administration and type of adjuvant systemic therapy separately. As suggested by the apparent dependence of prognostic impact of FGFR4 Arg388 genotype on nodal status, a significant survival impact of FGFR4 was indeed found only in patients with adjuvant systemic therapy. Interestingly, this survival difference favoring FGFR4 wild type was more strongly evident in patients with chemotherapy than in patients with endocrine therapy alone. The molecular mechanism by which FGFR4 Arg388 polymorphism leads to a more aggressive clinical phenotype is not yet fully understood. Similar mutations in the transmembrane domain of HER2 or FGFR3 result in increased tyrosine kinase activity and are associated with cellular transformation and developmental disorders. However, for FGFR4 Arg388, no elevated tyrosine phosphorylation was observed compared with FGFR4 Gly388 in breast and prostate cancer cells.23 This might indicate that changes in kinase activity are too subtle to detect differences reliably. Alternatively, the two polymorphic FGFR4 forms may use different intracellular signal transduction pathways or interact with different cell surface proteins. FGFR4 Arg388 allele may also be in linkage disequilibrium with other genetic changes that contribute to poor prognosis in breast cancer. Yet, cancer cells ectopically expressing FGFR4 Arg388 do possess increased cell motility and invasiveness, both characteristic of an aggressive tumor phenotype.23,33 Moreover, urokinase-receptor (uPAR) expression is increased in prostate epithelial cells expressing the FGFR4 Arg388 allele compared with FGFR4 Gly388 allele–expressing cells.33 uPAR is the cell-surface receptor for the urokinase-type plasminogen activator/plasminogen activator inhibitor type 1 system, playing a key role in breast cancer progression.34 Furthermore, urokinase-type plasminogen activator downregulation sensitizes tumor cells to chemotherapy-induced apoptosis.35 This background is particularly important, because one aspect in chemotherapy failure is tumor cell resistance to induction of apoptosis. Therefore, possible explanations for the impact of FGFR4 Arg388 allele on disease progression in patients with adjuvant chemotherapy include either increased expression of antiapoptotic factors or downregulation of proapoptotic factors in cells expressing FGFR4 Gly388 allele, as observed in previous investigations for promigration factors (J. Bange, unpublished results).
Recent data by Jezequel et al29 show no prognostic impact of FGFR4. These apparently conflicting results may well be attributed to differences in the patient cohorts, particularly regarding systemic therapy. Whereas their node-negative cohort was similar to ours regarding absence of adjuvant systemic therapy, systemic treatment of their node-positive cohort was different. Their chemotherapy consisted solely of anthracycline-based therapy, whereas less than 30% of our patients received anthracyclines. Moreover, our anthracycline-treated patients received a higher weekly dose ( In conclusion, the initially observed genotype-dependent difference in disease progression in node-positive patients had at first suggested FGFR4 as a pure marker for tumor aggressiveness, subdividing patients with advanced breast cancer into those with good or poor outcome. Our new findings with regard to survival differences dependent on administration and type of adjuvant systemic therapy point toward a much more complex role of FGFR4 in tumor progression. This new understanding could thus impact basic research as well as clinical management, potentially leading to differential strategies in therapy design.
The authors indicated no potential conflicts of interest.
We thank Anette Haas and Daniela Hellmann for their excellent technical assistance.
published online ahead of print at www.jco.org on July 5, 2006. Supported by grants from Universal Mobile Telecommunications System (# 01GS0105, part 11) to H.H. and A.U., as well as the State of Bavaria (KKF Project # 8756159) and the Wilhelm Sander Foundation (2000.017.2) to N.H. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Survival curves were plotted according to Kaplan-Meier; DFS was of primary interest, since it best reflects impact of adjuvant systemic therapy. The proportional hazards model was tested graphically; comparison between groups was performed by log-rank test. Forward stepwise Cox regression was used for multivariate survival modeling, with linear terms in first block and interactions in second block. Analyses were performed using SPSS 12.0.1 (SPSS Inc, Chicago, IL). 
30 mg/m2). Hence, resistance to adjuvant therapy observed in our cohort could be associated with certain adjuvant therapy types, particularly CMF-based chemotherapy. This issue deserves further study. 
