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01-02-2018 | Clinical trial

Expression of Cyclin D1 protein in residual tumor after neoadjuvant chemotherapy for breast cancer

Authors: S. L. Villegas, S. Darb-Esfahani, G. von Minckwitz, J. Huober, K. Weber, F. Marmé, J. Furlanetto, C. Schem, B. M. Pfitzner, B. Lederer, K. Engels, S. Kümmel, V. Müller, K. Mehta, C. Denkert, S. Loibl

Published in: Breast Cancer Research and Treatment | Issue 1/2018

Abstract

Purpose

Hormone receptor (HR)-positive breast cancer (BC) shows a poor response to neoadjuvant chemotherapy (NACT). New treatment targets like the Cyclin D1-CDK4/CDK6 complex are promising adjuvant/post-neoadjuvant therapeutic strategies. Evaluating Cyclin D1 overexpression in residual tumor could recognize those patients that benefit most from such post-neoadjuvant treatment. In this study, we determined Cyclin D1 expression in residual BC after NACT. Secondary aims were to correlate Cyclin D1 expression levels with clinicopathological parameters and to assess its prognostic value after NACT.

Methods

We retrospectively assessed the nuclear expression of Cyclin D1 on tissue microarrays with residual tumor from 284 patients treated in the neoadjuvant GeparTrio (n = 186) and GeparQuattro (n = 98) trials. Evaluation was performed with a standardized immunoreactive score (IRS) after selecting a cut-off value.

Results

A high expression level (IRS ≥ 6) of Cyclin D1 was found in 37.3% of the assessed specimens. An increased Cyclin D1 expression was observed in HR-positive tumors, compared to HR-negative tumors (p = 0.02). Low Cyclin D1 levels correlated with clinical tumor stage 1–3 (p = 0.03). Among patients with HR-positive/Her2-negative tumors and high Cyclin D1 expression, a better disease-free survival (DFS) was graphically suggested, but not significant (p = 0.21).

Conclusion

Our study demonstrates a measurable nuclear expression of Cyclin D1 in post-neoadjuvant residual tumor tissue of HR-positive BC. Cyclin D1 expression was not prognostic for DFS after NACT. Our results and defined cut-off suggest that the marker can be used to stratify tumors according to protein expression levels. Based on this, a prospective evaluation is currently performed in the ongoing Penelope-B trial.

Ferlay JSI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. (2013) Cancer incidence and mortality worldwide. Int Agency Res Cancer. http://globocan.iarc.fr. Accessed 11 Nov 2015

Kummel S, Holtschmidt J, Loibl S (2014) Surgical treatment of primary breast cancer in the neoadjuvant setting. Br J Surg 101(8):912–924. https://doi.org/10.1002/bjs.9545 CrossRefPubMed

Berruti A, Amoroso V, Gallo F, Bertaglia V, Simoncini E, Pedersini R, Ferrari L, Bottini A, Bruzzi P, Sormani MP (2014) Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. J Clin Oncol 32(34):3883–3891. https://doi.org/10.1200/JCO.2014.55.2836 CrossRefPubMed

Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE Jr, Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384(9938):164–172. https://doi.org/10.1016/S0140-6736(13)62422-8 CrossRefPubMed

von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30(15):1796–1804. https://doi.org/10.1200/JCO.2011.38.8595 CrossRef

Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, Dumontet C, Reed J, Krajewska M, Treilleux I, Rupin M, Magherini E, Mackey J, Martin M, Vogel C (2009) Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 27(8):1168–1176. https://doi.org/10.1200/JCO.2008.18.1024 CrossRefPubMedPubMedCentral

von Minckwitz G, Schmitt WD, Loibl S, Muller BM, Blohmer JU, Sinn BV, Eidtmann H, Eiermann W, Gerber B, Tesch H, Hilfrich J, Huober J, Fehm T, Barinoff J, Rudiger T, Erbstoesser E, Fasching PA, Karn T, Muller V, Jackisch C, Denkert C (2013) Ki67 measured after neoadjuvant chemotherapy for primary breast cancer. Clin Cancer Res 19(16):4521–4531. https://doi.org/10.1158/1078-0432.CCR-12-3628 CrossRef

Creighton CJ (2012) The molecular profile of luminal B breast cancer. Biologics 6:289–297. https://doi.org/10.2147/BTT.S29923 PubMedPubMedCentral

Herschkowitz JI, He X, Fan C, Perou CM (2008) The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res 10(5):R75. https://doi.org/10.1186/bcr2142 CrossRefPubMedPubMedCentral

10.

Witkiewicz AK, Knudsen ES (2014) Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions. Breast Cancer Res. https://doi.org/10.1186/Bcr3652 PubMedPubMedCentral

11.

Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ (2009) PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. https://doi.org/10.1186/Bcr2419 PubMedPubMedCentral

12.

Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, Tilley A, Zirkelbach JF, Yu JY, Liu Q, Zhao L, Crich J, Chen XH, Hughes M, Bloomquist E, Tang SH, Sridhara R, Kluetz PG, Kim G, Ibrahim A, Pazdur R, Cortazar P (2015) FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, her2-negative metastatic breast cancer. Clin Cancer Res 21(21):4760–4766. https://doi.org/10.1158/1078-0432.CCR-15-1185 CrossRefPubMed

13.

von Minckwitz G, Bear H, Bonnefoi H, Colleoni M, Gelmon K, Gnant M, Kim S-B, Loibl S, Makris A, Martin M, Nekljudova V, Rugo H, Saini K, Toi M, Untch M, Werutsky G (2013) Abstract OT2-6-11: PENELOPE: Phase III study evaluating palbociclib (PD-0332991), a cyclin-dependent kinase (CDK) 4/6 inhibitor in patients with hormone-receptor-positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemoth Cancer Research 73 (24 Supplement):OT2-6-11-OT12-16-11. https://doi.org/10.1158/0008-5472.sabcs13-ot2-6-11

14.

Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993) Cyclin D1 Is a nuclear-protein required for cell-cycle progression in G(1). Genes Dev 7(5):812–821. https://doi.org/10.1101/Gad.7.5.812 CrossRefPubMed

15.

Bagchi S, Weinmann R, Raychaudhuri P (1991) The retinoblastoma protein copurifies with e2f-i, an e1a-regulated inhibitor of the transcription factor E2f. Cell 65(6):1063–1072. https://doi.org/10.1016/0092-8674(91)90558-G CrossRefPubMed

16.

Buchkovich K, Duffy LA, Harlow E (1989) The retinoblastoma protein is phosphorylated during specific phases of the cell-cycle. Cell 58(6):1097–1105. https://doi.org/10.1016/0092-8674(89)90508-4 CrossRefPubMed

17.

Murphree AB, William F (1984) Retinoblastoma: clues to human oncogenesis. Science 223:1028–1033CrossRefPubMed

18.

Burkhart DL, Sage J (2008) Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 8(9):671–682. https://doi.org/10.1038/nrc2399 CrossRefPubMed

19.

Lee EYHP, To H, Shew JY, Bookstein R, Scully P, Lee WH (1988) Inactivation of the retinoblastoma susceptibility gene in human-breast cancers. Science 241(4862):218–221. https://doi.org/10.1126/science.3388033 CrossRefPubMed

20.

Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES (2010) RB-pathway disruption in breast cancer differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle 9(20):4153–4163. https://doi.org/10.4161/cc.9.20.13454 CrossRefPubMedPubMedCentral

21.

Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CK, Musgrove EA, Sutherland RL (1993) Expression and amplification of cyclin genes in human breast cancer. Oncogene 8(8):2127–2133PubMed

22.

McIntosh GG, Anderson JJ, Milton I, Steward M, Parr AH, Thomas MD, Henry JA, Angus B, Lennard TW, Horne CH (1995) Determination of the prognostic value of Cyclin D1 overexpression in breast cancer. Oncogene 11(5):885–891PubMed

23.

Bartkova J, Lukas J, Muller H, Lutzhoft D, Strauss M, Bartek J (1994) Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 57(3):353–361CrossRefPubMed

24.

von Minckwitz G, Kummel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, Gerber B, Huober J, Costa SD, Jackisch C, Loibl S, Mehta K, Kaufmann M, German Breast G (2008) Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst 100(8):542–551. https://doi.org/10.1093/jnci/djn085 CrossRef

25.

von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Kuhn T, du Bois A, Blohmer JU, Thomssen C, Dan Costa S, Jackisch C, Kaufmann M, Mehta K, Untch M (2010) Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol 28(12):2015–2023. https://doi.org/10.1200/JCO.2009.23.8303 CrossRef

26.

Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Der Pathologe 8(3):138–140PubMed

27.

Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, Denkert C (2012) Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE 7(12):e51862. https://doi.org/10.1371/journal.pone.0051862 CrossRefPubMedPubMedCentral

28.

Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF, American Society of Clinical Oncology, College of American P (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25(1):118–145. https://doi.org/10.1200/JCO.2006.09.2775

29.

Denkert C, Loibl S, Muller BM, Eidtmann H, Schmitt WD, Eiermann W, Gerber B, Tesch H, Hilfrich J, Huober J, Fehm T, Barinoff J, Jackisch C, Prinzler J, Rudiger T, Erbstosser E, Blohmer JU, Budczies J, Mehta KM, von Minckwitz G (2013) Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial. Ann Oncol 24(11):2786–2793. https://doi.org/10.1093/annonc/mdt350 CrossRefPubMed

30.

Barbareschi M, Pelosio P, Caffo O, Buttitta F, Pellegrini S, Barbazza R, Dalla Palma P, Bevilacqua G, Marchetti A (1997) Cyclin D1-gene amplification and expression in breast carcinoma: relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21WAF1 immunohistochemical expression. Int J Cancer 74(2):171–174CrossRefPubMed

31.

Reis-Filho JS, Savage K, Lambros MB, James M, Steele D, Jones RL, Dowsett M (2006) Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 19 (7):999–1009. https://doi.org/doi:10.1038/modpathol.3800621

32.

Peurala E, Koivunen P, Haapasaari KM, Bloigu R, Jukkola-Vuorinen A (2013) The prognostic significance and value of Cyclin D1, CDK4 and p16 in human breast cancer. Breast Cancer Res 15(1):R5. https://doi.org/10.1186/bcr3376 CrossRefPubMedPubMedCentral

33.

Remmele W, Stegner HE (1987) A proposal for the standardization of the immunoreactive score (Irs) for the Immunohistochemical Demonstration of Estrogen-Receptors (Er-Ica) in Breast-Cancer. Der Pathologe 8(3):138–140PubMed

34.

Specht E, Kaemmerer D, Sanger J, Wirtz RM, Schulz S, Lupp A (2015) Comparison of immunoreactive score, HER2/neu score and H score for the immunohistochemical evaluation of somatostatin receptors in bronchopulmonary neuroendocrine neoplasms. Histopathology 67(3):368–377. https://doi.org/10.1111/his.12662 CrossRefPubMed

35.

Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17(5):1474–1481CrossRefPubMed

36.

Li Z, Cui J, Yu Q, Wu X, Pan A, Li L (2016) Evaluation of CCND1 amplification and Cyclin D1 expression: diffuse and strong staining of Cyclin D1 could have same predictive roles as CCND1 amplification in ER positive breast cancers. Am J Transl Res 8(1):142–153PubMedPubMedCentral

37.

Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ (2009) PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 11(5):R77. https://doi.org/10.1186/bcr2419 CrossRefPubMedPubMedCentral

38.

Li XR, Liu M, Zhang YJ, Wang JD, Zheng YQ, Li J, Ma B, Song X (2011) Evaluation of ER, PgR, HER-2, Ki-67, cyclin D1, and nm23-H1 as predictors of pathological complete response to neoadjuvant chemotherapy for locally advanced breast cancer. Med Oncol 28(Suppl 1):S31–S38. https://doi.org/10.1007/s12032-010-9676-z CrossRefPubMed

39.

Penault-Llorca F, Abrial C, Raoelfils I, Chollet P, Cayre A, Mouret-Reynier MA, Thivat E, Mishellany F, Gimbergues P, Durando X (2008) Changes and predictive and prognostic value of the mitotic index, Ki-67, Cyclin D1, and cyclo-oxygenase-2 in 710 operable breast cancer patients treated with neoadjuvant chemotherapy. Oncologist 13(12):1235–1245. https://doi.org/10.1634/theoncologist.2008-0073 CrossRefPubMed

40.

Gillett C, Smith P, Gregory W, Richards M, Millis R, Peters G, Barnes D (1996) Cyclin D1 and prognosis in human breast cancer. Int J Cancer 69(2):92–99CrossRefPubMed

41.

Chung J, Noh H, Park KH, Choi E, Han A (2014) Longer survival in patients with breast cancer with Cyclin D1 over-expression after tumor recurrence: longer, but occupied with disease. J Breast Cancer 17(1):47–53. https://doi.org/10.4048/jbc.2014.17.1.47 CrossRefPubMedPubMedCentral

42.

Kenny FS, Hui R, Musgrove EA, Gee JMW, Blamey RW, Nicholson RI, Sutherland RL, Robertson JFR (1999) Overexpression of Cyclin D1 messenger RNA predicts for Poor prognosis in estrogen receptor-positive breast cancer. Clin Cancer Res 5(8):2069–2076PubMed

43.

Courjal F, Louason G, Speiser P, Katsaros D, Zeillinger R, Theillet C (1996) Cyclin gene amplification and overexpression in breast and ovarian cancers: evidence for the selection of Cyclin D1 in breast and cyclin E in ovarian tumors. Int J Cancer 69(4):247–253CrossRefPubMed

44.

Xu XL, Chen SZ, Chen W, Zheng WH, Xia XH, Yang HJ, Li B, Mao WM (2013) The impact of cyclin D1 overexpression on the prognosis of ER-positive breast cancers: a meta-analysis. Breast Cancer Res Treat 139(2):329–339. https://doi.org/10.1007/s10549-013-2563-5 CrossRefPubMed

Title: Expression of Cyclin D1 protein in residual tumor after neoadjuvant chemotherapy for breast cancer
Authors: S. L. Villegas
S. Darb-Esfahani
G. von Minckwitz
J. Huober
K. Weber
F. Marmé
J. Furlanetto
C. Schem
B. M. Pfitzner
B. Lederer
K. Engels
S. Kümmel
V. Müller
K. Mehta
C. Denkert
S. Loibl
Publication date: 01-02-2018
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-017-4581-1

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