|Year : 2021 | Volume
| Issue : 2 | Page : 254-260
|Fibroblast growth factor receptor 1 protein (FGFR1) as potential prognostic and predictive marker in patients with luminal B breast cancers overexpressing human epidermal receptor 2 protein (HER2)
Belhadj Amina1, Addou Klouche Lynda2, Seddiki Sonia1, Belhadj Adel3, Benammar H Jelloul4, Medjamia Miloud5, Sahraoui Tewfik1
1 Biology of Development and Differentiation Laboratory, Oran 1 University, Ahmed Ben Bella, Oran, Algeria
2 Biotoxicology Laboratory, Sidi Bel Abbes University, Oran, Algeria
3 Medecine Faculty, Oran 1 University, Ahmed Ben Bella, Oran, Algeria
4 Anatomy and Cytopathology Laboratory, Sidi Bel Abbes, Oran, Algeria
5 Anatomy and Cytopathology Laboratory, Regional Military Hospital University, Oran, Algeria
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|Date of Submission||19-Feb-2020|
|Date of Decision||15-May-2020|
|Date of Acceptance||21-Jul-2020|
|Date of Web Publication||9-Apr-2021|
| Abstract|| |
Context: Breast cancer is the most common cause of cancer mortality among women worldwide. It is a heterogeneous disease partly responsible for treatment failure in luminal B patients. Deregulation of fibroblast growth factor signaling has been found and its therapeutic/prognostic value is explored. Aims: Most of the research has studied the FGFR1 gene while our study explored its protein expression by immunohistochemestry and examined the association with clinicopathological features, different molecular subtypes and survival. Subjects and Methods: Formalin-fixed and paraffin-embedded samples of invasive breast carcinomas were used to analyze FGFR1 expression. FGFR 1 was scored by percentage and intensity of cell cytoplasm staining, correlations were investigated and survival curves were constructed. Statistical Analysis Used: Chi-square test was used to assess the relationship between the marker expression and the clinicopathological characteristics. Overall specific survival curves were estimated using the Kaplan-Meier method and statistical significance was assessed using the log-rank test. Results: FGFR1 was associated at different staining threshold cut-offs with tumor size (P = 0.002), infiltrating lymph node (P = 0.022), distant metastasis (P = 0.003), positive estrogen receptor (P = 0.000), HER2 overexpression (P = 0.044) and luminal phenotypes (P = 0.026). The results also emphasize FGFR1 correlation expression with distant metastasis in luminal B tumors (P = 0.035) but not with luminal A and with overexpressed HER2 protein in both luminal tumors. FGFR1 expression affect luminal B patients survival with poor outcome. Conclusions: FGFR1 expression may serve as a prognostic and predictive factor in luminal breast cancers, it can also be considered as a potential therapeutic target in luminal B cases.
Keywords: Breast cancer, fibroblast growth factor receptor 1 (FGFR1), luminal B, predictive marker
|How to cite this article:|
Amina B, Lynda AK, Sonia S, Adel B, Jelloul BH, Miloud M, Tewfik S. Fibroblast growth factor receptor 1 protein (FGFR1) as potential prognostic and predictive marker in patients with luminal B breast cancers overexpressing human epidermal receptor 2 protein (HER2). Indian J Pathol Microbiol 2021;64:254-60
|How to cite this URL:|
Amina B, Lynda AK, Sonia S, Adel B, Jelloul BH, Miloud M, Tewfik S. Fibroblast growth factor receptor 1 protein (FGFR1) as potential prognostic and predictive marker in patients with luminal B breast cancers overexpressing human epidermal receptor 2 protein (HER2). Indian J Pathol Microbiol [serial online] 2021 [cited 2021 May 8];64:254-60. Available from: https://www.ijpmonline.org/text.asp?2021/64/2/254/313302
| Introduction|| |
The fibroblast growth factor receptor (FGFR) gene codes for one of the FGFR tyrosine kinase (TK) receptor family which are: FGFR1, 2, 3, and 4, located on chromosomes 8p12, 10q26, 4p16.3 and 5q35.1-qter, respectively.
FGFR TK have an essential role in cell development and are fundamental to regulation of angiogenesisis., In cancers, FGFRs are deregulated by amplification, point mutation, or translocation. Abberant FGFR signaling is implicated in solid tumors,,,,, in particular the epidermoid form of lung cancer and breast cancer.,,,
The development and progression of breast cancer is the result of genetic and epigenetics alterations. Some reports have demonstrated that FGFR1 was shown to be amplified,, in approximately 10% of all breast cancers. they are frequently ER positive with high proliferation rate and are present in 16 to 27% of luminal-B subtype,, knowing that the subtypes of breast cancer most in need of therapeutic advances are basal-like and luminal-B.
| Subjects and Methods|| |
Patients and database
This study was approved by our institutional review board, we obtained 62 archived formalin fixed, paraffin-embedded material from surgically resected breast cancer specimens containing tumor tissues from the military hospital of Oran. These tumors were from female patients who underwent radical mastectomy from January 2009 to December 2014. The clinical characteristics and outcome data were recorded by reviewing patient's medical reports. The patients were aged from 27-88 years with a median age of 49 years old ± 13.05. We excluded from this study the absence of tumoral tissues and male gender patients.
Immunohostochemical staining and evaluation
The formalin-fixed, paraffin-embedded tissue sections (3-Am-thick) were deparaffinized and hydrated washed once in H2O for 5 minutes and then incubated in target retrieval solution Citrate (pH 6.0) in a boiling water-bath for 50 minutes.
The slides were cooled for 20 minutes. Following washing in phosphate-buffered saline (PBS), slides were incubated with 3% hydrogen peroxide in methanol for 10 min to block endogenous peroxidase activity and washed again in H2O for 5 minutes and then incubated with a blocking serum for 10 minute.
The slides were incubated in primary antibody for 1 hour, washed in PBS for 5 minutes, then incubated in secondary antibody (Dako REAL™ EnVision™ Detection System) at room temperature for 30 minutes. The slides were washed and developed in 3,30-diaminobenzidine (Peroxidase_DAB, Rabbit_Mouse purchased from Dako.) under microscopic observation. The reaction was stopped in tap water and the tissues were counterstained with Mayer's hematoxylin, dehydrated, and mounted. The images were taken using Leica DFC 280 (Leica DM LB2). The expression was quantified blindly by two observers.
For this study we used monoclonal antibodies at a dilution of 1 :500 for FGFR1 (Clone (D8E4) XP, Cell signaling), additional markers were examined including hormonal receptors ER (Clone 1D5, Dako, dilution: 1:100) and PR (Clone PgR 636, Dako, dilution: 1:00) and other common cancer markers HER 2 (Clone PN2A, Dako, dilution: 1:100 ) and Ki67 (Clone MIB-1; Dako, dilution: 1:100).
The classification of positive immunoreactivity in tumor cells was carried out according to the percentage of immunopositive cells: <10% was classified as negative and >10% as positive for ER and PR nuclear markers.
Membranous immunoreactivity of HER2 was scored as follows: 0 and 1+ indicates negative; 2+, indeterminate; and 3+, positive for overexpression. Ki67 expression was assessed to distinguish between luminal A and luminal B breast cancer. The cut off Ki67 value was ≥14% as previously reported.
The assessment of FGFR1 staining was based on a previous study, immunostained slides were scored for cytoplasmic staining by intensity (intensity scores 1 as [weak], 2 as [moderate], 3 as [strong]) and percentage of invasive tumor cells stained for each intensity. H-score was defined by using the formula: (3 X percentage strong staining) + (2 X percentage moderate staining) + (1 X percentage weak staining). We selected two cut-off values: unequivocal staining of any intensity in at least 1% of the tumor cells and H-score of 100 or more. These cut-off values were selected to evaluate our study cohort by almost complete negative expression and high expression of FGFR1. In addition, all cases were classified into molecular subtypes basing on immunohistochemestry (IHC) surrogates, listed as follows:
Luminal A: ER+, PR+/-, HER2+/-, Ki67 <14%
Luminal B: ER+, RP+/-, HER2+/-, Ki67 ≥14%
Triple-negative breast cancer (TNBC) : ER-, PR-, HER2-
HER2 subtype : ER-, PR-, HER2+.
All statistical analysis was processed using SPSS 25 (Statistical Package for the Social Sciences, IBM Corporation; Chicago, IL). Results are expressed as means ± standard deviations and percentages. The Chi-Square test was used to assess the relationship between the marker expression and the main clinicopathological characteristics including age, histology type, SBR grade, TNM stage, molecular classification. Overall specific survival (OS) curves were estimated using the Kaplan-Meier method and statistical significance was assessed using the log-rank test. OS follow-up times were measured from the date of diagnosis till death or to the end of the study. Statistical significance was determined with P < 0.05. Any significant findings can serve as hypothesis generation and require further confirmation in future studies.
| Results|| |
A total of 62 primary invasive breast cancers were included in this cohort. Detailed clinical and pathological information were available in most cases and are summarized in [Table 1]. Missing values were mainly due to unavailable information after review of histological specimens and pathological reports. The mean age was 51.56 ± 13.05 years (range 27–88).
BC subtype was assigned based on IHC staining of 62 invasive cancers with complete data for IHC based molecular classification, 19 (30.6%) were Lum A, 19 (30.6%) were Lum B, 8 (13%) were HER2+ and 16 (25.8%) were TNBC.
|Table 1: Clinicopathological characteristics and their frequencies among 62 patients with breast carcinomas|
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FGFR1 association with clinical and molecular features
FGFR1 immunohistochemestry assessment by frequency of cases across various staining thresholds is tabulated in [Table 2], majority of tumors were negative. Representative FGFR1 staining is shown in [Figure 1].
|Table 2: Distribution of FGFR1 immunostaining at different cut-off thresholds|
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|Figure 1: Cytoplasmic immunohistochemical stainings of FGFR1. (a) Invasive carcinoma with negative FGFR 1 cytoplasmic staining. (b) Invasive carcinoma with weak FGFR 1 cytoplasmic staining. (c) Invasive carcinoma with weak FGFR1 cytoplasmic staining. (d) Invasive carcinoma with strong FGFR1 cytoplasmic staining|
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The results of FGFR1 associations with clinicopathological characteristics are shown in [Table 3]. FGFR1 expression was found to be associated across both staining threshold cut-offs with high lymph node status (P = 0.059 and P = 0.022) but not with age, SBR grade, PR and Ki67status. There were a positive association with ER status ( P = 0.000), HER2 status (P = 0.044) and luminal tumors (P = 0.026) when FGFR1 H-score was higher than 100, a P values close to significant were noted for these parameters when FGFR1 was present in at least 1% of tumor cytoplasm (P = 0.061 for each). FGFR1 staining was also significantly correlated with histological type and distant metastasis (P = 0.000, P = 0.003 respectively), Indeed, There was a higher proportion of luminal B tumors stained positively for FGFR1 staining in at least 1% of tumor cytoplasm compared to luminal-A tumors, we also noted loss of FGFR1 expression in HER2+ and TNBC tumors for FGFR1 staining at H-score of 100 or more [Table 3].
|Table 3: Association of FGFR1 expression and clinicopathological features at different cut-off thresholds|
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FGFR1 expression in luminal tumors
Considering the results obtained with regard molecular phenotypes, in particular luminal tumors, it was interesting to explore the relationship of FGFR1 with the histoclinical features.
FGFR1 was expressed in 5 out of 19 cases (26.31%) and 11 out of 19 cases (57.89%) of luminal A and luminal B cancers respectively. FGFR1 expression has been associated with pathological tumpor size (P = 0.005) and with HER2 expression at both thresholds (P = 0.013 and P = 0.008) in luminal A tumors, whereas, luminal B subtype show positive correlations with distant metastasis and HER2 expression (P = 0.035, P = 0.026 respectively) [Table 4]. No other clinicopathological feature has exhibited a significant correlation with FGFR1 protein expression.
|Table 4: FGFR1 association with clinicopathological features according to different luminal subtypes|
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The OS curves of luminal/HER2+ tumors are calculated by the Kaplan-Meier method according to FGFR1 expression (positive when immunohistochemical staining was detected in at least 1% of the cytoplasm cells) are shown in [Figure 2]. FGFR1 expression was significantly associated with luminal B/HER2+ OS tumors (Log-rank = 4, P = 0.049) but not with luminal A/HER2+ tumors (P = 0.480), and the median OS time was 6 months for the FGFR1-negative group and 10 months for the FGFR1-positive group. The results indicated that patients with positive FGFR1 expression exhibited a significantly longer survival time than those with negative FGFR1 expression in luminal B/HER2+ cases (DFS is not significant and not shown
|Figure 2: Kaplan-Meier survival analysis of overall survival rate performed by log-rank statistics. (a) OS at FGFR1 cytoplasmic immunoreactivity of at least 1% staining among luminal A/ HER2+ tumors. (b) OS at FGFR1 cytoplasmic immunoreactivity of at least 1% staining among luminal B/HER2+ tumors|
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| Discussion|| |
Fibroblast growth factor receptors have been shown to play important roles in breast cancer,,, moreover FGFR1 was one of the first genes to be shown to be amplified in breast cancer, amplified in ∼10% cancers. Furthermore, some studies have found that FGFR1 expression correlates with FGFR1 amplification,, but others have not,, these discrepancies in the available data in addition to the fact that to date there have been few studies focuses on its protein expression in breast cancer except for Shi and collaborator, while, Lee et al. and Cheng et al. focused their studies on TNBCs samples , led us to investigate FGFR1 protein expression association with Algerian patient's clinicopathological features as well as with the breast cancer groups. We chose to use the two thresholds of FGFR1 positivity in order to have maximum details and significance about its association with the different parameters and in survival curves.
Our data is consistent with previous report demonstrating a significant correlation between FGFR1 expression and multiple relevant clinicopathological features regarding, tumor size, histological type, estrogen receptor status and also molecular phenotype.
The overall FGFR1 expression rate in breast cancer was 11.2% at H-score more than 100 and 37.1% when at least 1% of cytoplasm cells were immunopositive, occurring predominantly in luminal B cancers (47.8%) with a significant association, this observation was concordant with its reported gene amplification in an anterior study demonstrating that FGFR1-amplified cancers are frequently PR-negative, have a high proliferation rate assessed by Ki-67 immunostaining and are present in 16 to 27% of luminal-B breast cancer.
In the work presented here we observed a positive association with ER expression and the high lymph node infiltrating which are a poor prognostic factors, this, corroborated its prevalence in luminal B cancer subtype. However, its expression at different thresholds cut-offs did not significantly affect patient survival (data not shown).
Our results are consistent with those of Issa et al. demonstrating the co-expression of FGFR1 and HER2 proteins. Indeed, some breast tumors with copy number changes in both ERBB2 and FGFR1 were previously described. Moreover, concerning therapy strategies, it has been noted that combinatorial inhibition of FGFR and ErbB receptors has a very significant impact on the in vivo tumor growth and metastatic spread of breast cancer models, considering the emerging evidence that breast tumors co-express ErbB and FGFRs.
Increased FGFR1 levels are observed in several metastatic disease such as in brain cancer; prostate cancer and in tong squamous cell carcinoma. In our work, Nearly, similar rates of breast cancer metastasis were observed in patients overexpressing FGFR1 protein than in study with amplified FGFR1 gene. Brunello et al. found that FGFR1 gene was amplified and gained in 20% and 40%, respectively, of primary invasive lobular cancer with metastasis, in parallel, previous study demonstrates that amplification of FGFR1 or FGF3 has been detected in approximately 10% or 15% of primary tumors respectively, while patients with FGFR1 amplification are more likely to develop distant metastasis.
FGFR1signaling can cause persistent MAPK activation and its amplification was shown to be associated with poor outcome as well as a shorter disease-free survival in luminal type breast cancers and resistance to endocrine therapy.,, Shi et al., examined FGFR1 protein expression in 1,093 primary invasive breast cancers and found that poor outcome were mainly observed in luminal cancers (DFS: log-rank = 8.939, P = 0.003; OS: log-rank = 4.211, P = 0.040) with the same worse DFS in FGFR1 expressing among luminal A and luminal B cancers, our data are consistent with these previous reports, indeed, the relationship of FGFR1 expression with multiple relevant clinicopathologic features, tumor biomarker panels as well as the prognostic value in different luminal subtypes of breast cancers was investigated, demonstrating that FGFR1 has a prognostic impact on the luminal tumors exclusively the luminal B ones with the observed significant correlations with poor prognosis factors , namely, the presence of distant metastasis and HER2 overexpressed protein.
| Conclusions|| |
In conclusion, we demonstrated that FGFR1 protein expression was significantly deregulated in luminal B/HER2+ breast cancer tumors with a poor outcome, this, could serve as a predictive marker in breast cancers and might be an interesting therapeutic target for luminal B breast cancer subtype. The most recent promising preclinical study have identified a new selective FGFR inhibitor, C11, and assessed its antitumoral activities, this finding may opens prospects to target FGFR1 protein in particluar in mammary tumors with luminal B phenotype as in the case of HER2+ breast tumors.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Biology of Development and Differentiation Laboratory, Oran 1 University, Ahmed Ben Bella
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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