Abstract
The goal of the present study was to evaluate the role of the tyrosine kinase receptor fibroblast growth factor-1 (FGFR1) and its ligand, the fibroblast growth factor 2 (FGF2) in determining the response to chemoradiotherapy of breast cancers. S14 was a phase II neoadjuvant study carried out at the Institut Curie that recruited 59 patients between November 2001 and September 2003. This prospective study aimed to assess the pathological response after preoperative radiochemotherapy (5FU–Navelbine-radiotherapy) for large breast cancers. The expression of FGFR1 and FGF2 in tumor cells were assessed by immunohistochemistry. Tumors in which no staining was seen, were considered as negative for that protein. We used the Khi-2 test or the Fisher test to compare the qualitative variables and the Student t test or the non-parametric Wilcoxon test for the quantitative variables. We included in the present study all the 32 patients from the S14 cohort for whom the tissue blocks from the biopsy specimens were available with sufficient tumoral tissue. FGFR1 and FGF2 staining were observed respectively in 17 (56 %) and 22 (68 %) of the 32 tumoral biopsies. The expression of FGFR1 was associated with the hormone receptor positive status (p = 0.0191). Only 11 % (1/9) of the high grade tumors failed to respond to chemoradiotherapy compared to 68 % resistant tumors (15/22) among the low/intermediate grade tumors (p = 0.0199). Among the low/intermediate grade tumors, FGFR1 negative tumors did not respond to chemoradiotherapy (0/9), compared with tumors expressing FGFR1 among which, almost one half had a good response (6/13) (p = 0.0167). Among the low and intermediate grade breast cancers, the FGFR1 negative tumors were resistant to chemoradiotherapy. The expression of FGFR1 in patients’ biopsies may serve as a marker of response to chemoradiotherapy.
Similar content being viewed by others
References
Xia F, Powell SN (2002) The molecular basis of radiosensitivity and chemosensitivity in the treatment of breast cancer. Semin Radiat Oncol 12(4):296–304 Review
Pusztai L et al (2003) Gene expression profiles obtained from single passage fine needle aspirations (FNA) of breast cancer reliably identify prognostic/predictive markers such as estrogen (ER) and HER-2 receptor status and reveal large scale molecular differences between ER-negative and ER-positive tumors. Clin Cancer Res 9:2406–2415
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S et al (2011) Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 12(378):1707–1716
Conger A, Luippold H (1957) Studies on the mechanism of acquired radioresistance in cancer. Cancer Res 17(9):897–903
Van Limbergen E, Van der Schueren E, Van den Bogaert W, Van Wing J (1990) Local control of operable breast cancer after radiotherapy alone. Eur J Cancer 26:674–679
Pierquin B, Owen R, Maylin C et al (1980) Radical radiation therapy of breast cancer. Int J Radial Oncol Biol Phys 6:17–24
Amalric R, Santamaria F, Robert F et al (1982) Radiation therapy with or without primary limited surgery for operable breast cancer: a 20- year experience at the Marseille Cancer Institute. Cancer 49:3, 34
Scholl SM, Fourquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, Dorval T, Palangié T, Jouve M, Beuzeboc P et al (1994) Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer 30A(5):645–652
Semiglazov VF, Topuzov EE, Bavli JL et al (1994) Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage IIb–IIIa breast cancer. Ann Oncol 5(7):591–597
Formenti SC, Volm M, Skinner KA et al (2003) Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin- based chemotherapy in locally advanced breast cancer: a phase I/II trial. J Clin Oncol 21:864–870
Bollet MA, Fourquet A et al (2006) Pathological response to preoperative concurrent chemoradiotherapy for breast cancer: results of a phase II study. Eur J Cancer 42(14):2286–2295
Dickson C, Spencer-Dene B, Dillon C, Fantl V (2000) Tyrosine kinase signalling in breast cancer: fibroblast growth factors and their receptors. Breast Cancer Res 2(3):191–196
Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10(2):116–129
Reis-Filho JS, Ashworth A et al (2006) FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clin Cancer Res 15 12(22):6652–6662
Andre F, Job B, Dessen P et al (2009) Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res 15:441–451
Turner N et al (2010) FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 70(5):2085–2094
Sataloff DM, Mason BA, Prestipino AJ et al (1995) Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg 180(3):297–306
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) Reporting recommendations for tumor marker prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235
Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19(5):403–410
Vincent-Salomon A, Le Doussal V et al (2003) Calibration of immunohistochemistry for assessment of HER2 in breast cancer: results of the French multicentre GEFPICS study. Histopathology 42(4):337–347
Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752
Blanckaert VD, Hebbar M, Louchez MM, Vilain MO, Schelling ME, Peyrat JP (1998) Basic fibroblast growth factor receptors and their prognostic value in human breast cancer. Clin Cancer Res 4(12):2939–2947
Hsia E, Richardson TP, Nugent MA (2003) Nuclear localization of basic fibroblast growth factor is mediated by heparan sulfate proteoglycans through protein kinase C signaling. J Cell Biochem 88:1214–1225
Genestie C, Zafrani B, Asselain B, Fourquet A, Rozan S, Validire P, Vincent-Salomon A, Sastre-Garau X (1998) Comparison of the prognostic value of Scarff-Bloom-Richardson and Nottingham histological grades in a series of 825 cases of breast cancer: major importance of the mitotic count as a component of both grading systems. Anticancer Res 18(1B):571–576
Formenti SC, Dunnington G, Uzieli B et al (1997) Original p53 status predicts for pathological response in locally advanced breast cancer patients treated preoperatively with continuous infusion 5-fluorouracil and radiation therapy. Int J Radiat Oncol Biol Phys 39:1059–1068
Ayers M, Symmans WF, Stec J, Damokosh AI, Clark E, Hess K, Lecocke M, Metivier J, Booser D, Ibrahim N, Valero V, Royce M, Arun B, Whitman G, Ross J, Sneige N, Hortobagyi GN, Pusztai L (2004) Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol 22(12):2284–2293
Hess KR, Anderson K, Symmans WF, Valero V, Ibrahim N, Mejia JA, Booser D, Theriault RL, Buzdar AU, Dempsey PJ, Rouzier R, Sneige N, Ross JS, Vidaurre T, Gómez HL, Hortobagyi GN, Pusztai L (2006) Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol 24(26):4236–4244
Thuerigen O, Schneeweiss A, Toedt G, Warnat P, Hahn M, Kramer H, Brors B, Rudlowski C, Benner A, Schuetz F, Tews B, Eils R, Sinn HP, Sohn C, Lichter P (2006) Gene expression signature predicting pathologic complete response with gemcitabine, epirubicin, and docetaxel in primary breast cancer. J Clin Oncol 24(12):1839–1845
Bauer JA, Chakravarthy AB, Pietenpol JA (2010) Identification of markers of taxane sensitivity using proteomic and genomic analyses of breast tumors from patients receiving neoadjuvant paclitaxel and radiation. Clin Cancer Res 16(2):681–690
Pinder, S.E., Murray S., Ellis I.O., Trihia H., Elston C.W., Gelber R.D., Goldhirsch A., Lindtner J., Cortes-Funes H., Simoncini E., Byrne M.J., Golouh R., Rudenstam C.M., Castiglione-Gertsch M. and Gusterson B.A. (1998) The importance of the histologic grade of invasive breast carcinoma and response to chemotherapy. Cancer 83(8):1529–1539
Von Minckwitz G, Raab G, Caputo A et al (2005) Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol 23(12):2676–2685
Ring AE, Smith IE, Ashley S et al (2004) Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer. Br J Cancer 91(12):2012–2017
Petit T, Wilt M, Velten M et al (2004) Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer 40(2):205–211
Rakha EA, Ellis IO (2007) An overview of assessment of prognostic and predictive factors in breast cancer needle core biopsy specimens. J Clin Pathol 60(12):1300–1306 Review
Connor CS, Tawfik OW, Joyce AJ et al (2002) A comparison of prognostic tumor markers obtained on image-guided breast biopsies and final surgical specimens. Am J Surg 184:322–324
Smith K, Fox SB, Whitehouse R et al (1999) Upregulation of basic fibroblast growth factor in breast carcinoma and its relationship to vascular density, oestrogen receptor, epidermal growth factor receptor and survival. Ann Oncol 10:707–713
Linder C, Bystom P, Engel G et al (1998) Correlation between basic fibroblast growth factor immunostaining of stromal cells and stromelysin-3 mRNA expression in human breast carcinoma. Br J Cancer 77:941–945
Penault-Llorca F, Bertucci F, Adélaïde J, Parc P, Coulier F, Jacquemier J, Birnbaum D, deLapeyrière O (1995) Expression of FGF and FGF receptor genes in human breast cancer. Int J Cancer 61(2):170–176
Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10(2):116–129 Review
Massabeau C, Rouquette I, Lauwers-Cances V, Mazières J, Bachaud JM, Armand JP, Delisle MB, Favre G, Toulas C, Cohen-Jonathan-Moyal E (2009) Basic fibroblast growth factor-2/beta3 integrin expression profile: signature of local progression after chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 75(3):696–702
Acknowledgments
The authors thank Sophie Dodier, Laurence Vaslin, Vincent Pennaneach, Tomasz Zaremba and André Nicolas for their substantial help with this study.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Massabeau, C., Sigal-Zafrani, B., Belin, L. et al. The fibroblast growth factor receptor 1 (FGFR1), a marker of response to chemoradiotherapy in breast cancer?. Breast Cancer Res Treat 134, 259–266 (2012). https://doi.org/10.1007/s10549-012-2027-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-012-2027-3