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01-10-2014 | Preclinical study

Transcriptional CCND1 expression as a predictor of poor response to neoadjuvant chemotherapy with trastuzumab in HER2-positive/ER-positive breast cancer

Authors: M. Tanioka, K. Sakai, T. Sudo, T. Sakuma, K. Kajimoto, K. Hirokaga, S. Takao, S. Negoro, H. Minami, K. Nakagawa, K. Nishio

Published in: Breast Cancer Research and Treatment | Issue 3/2014

Abstract

Several trials have confirmed that the pathological complete response (pCR) rates after neoadjuvant chemotherapy (NAC) are significantly lower in HER2-positive/ER-positive patients than in HER2-positive/ER-negative patients. To understand this phenomenon, we investigated the association between NAC resistance and CCND1, which is frequently overexpressed in ER-positive tumors. Pretreatment formalin-fixed tumor tissues were collected from 75 HER2-positive patients receiving NAC comprised anthracyclines, taxanes, and trastuzumab. Seventeen gene transcripts along with PIK3CA mutations were detected using MassARRAY (Sequenom, San Diego, CA). The gene expression levels were dichotomized according to the median values. The immunohistochemical expression of ER, PTEN, BCL-2, and cyclin D1 was scored. The relationship between the variables was assessed using the Spearman correlation. A logistic regression analysis was performed to detect predictors of pCR, which was defined as no invasive tumor in the breast or axilla. Forty-seven percent of the cases were ER-positive and 52 % (40/63 % in ER-positive/ER-negative) achieved a pCR. Among the ER-positive patients, the CCND1 gene expression level was 2.1 times higher than that in ER-negative patients and was significantly correlated with the expression of cyclin D1 protein. In a univariate analysis, a pCR was associated with high mRNA levels of ESR1, PGR, LMTK3, HER2, IGF1R, INPP4B, PDL-1, BCL-2, and CCND1 (P ≤ 0.05). In contrast, none of these genes were significantly correlated with a pCR among the ER-negative tumors and only EGFR was significantly correlated with a pCR. PIK3CA mutations or PTEN loss were not associated with a pCR in either group. After excluding ESR1 (r = 0.58), PGR (r = 0.64), and IGF1R (r = 0.59), the expressions of which were correlated with CCND1, a multivariate analysis revealed that CCND1 [P = 0.043; OR, 0.16] and HER2 [P = 0.012; OR, 11.2] retained its predictive value for pCR among ER-positive patients, but not among ER-negative patients. A High Level of CCND1 gene expression is a poor predictor of a pCR and provides a rationale for evaluating CDK4/6 inhibitors in HER2-positive/ER-positive breast cancer patients.

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. doi:10.1200/JCO.2011.38.8595 CrossRef

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:Epub 18/Feb/2014. doi:10.1016/S0140-6736(13)62422-8

Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N (2013) Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol 14(12):1183–1192. doi:10.1016/S1470-2045(13)70411-X PubMedCrossRef

Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gomez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horvath Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379(9816):633–640. doi:10.1016/S0140-6736(11)61847-3 PubMedCrossRef

Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13(1):25–32. doi:10.1016/S1470-2045(11)70336-9 PubMedCrossRef

Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, Pavlick AC, Wang T, Hilsenbeck SG, Gutierrez C, Schiff R, Osborne CK, Chang JC (2013) Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol 31(14):1726–1731. doi:10.1200/JCO.2012.44.8027 PubMedCrossRefPubMedCentral

Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, Gonzalez-Angulo AM, Hennessy BT, Mills GB, Kennedy JP, Lindsley CW, Arteaga CL (2009) Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res 69(10):4192–4201. doi:10.1158/0008-5472.CAN-09-0042 PubMedCrossRefPubMedCentral

Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm AV, Rasmussen LM, Riese DJ 2nd, de Cremoux P, Stenvang J, Lykkesfeldt AE (2009) Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat 114(2):263–275. doi:10.1007/s10549-008-0011-8 PubMedCrossRefPubMedCentral

Giltnane JM, Ryden L, Cregger M, Bendahl PO, Jirstrom K, Rimm DL (2007) Quantitative measurement of epidermal growth factor receptor is a negative predictive factor for tamoxifen response in hormone receptor positive premenopausal breast cancer. J Clin Oncol 25(21):3007–3014. doi:10.1200/JCO.2006.08.9938 PubMedCrossRef

10.

Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, Natrajan R, Marchio C, Iorns E, Mackay A, Gillett C, Grigoriadis A, Tutt A, Reis-Filho JS, Ashworth A (2010) FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 70(5):2085–2094. doi:10.1158/0008-5472.CAN-09-3746 PubMedCrossRefPubMedCentral

11.

Vaillant F, Merino D, Lee L, Breslin K, Pal B, Ritchie ME, Smyth GK, Christie M, Phillipson LJ, Burns CJ, Mann GB, Visvader JE, Lindeman GJ (2013) Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 24(1):120–129. doi:10.1016/j.ccr.2013.06.002 PubMedCrossRef

12.

Berns EM, van Staveren IL, Klijn JG, Foekens JA (1998) Predictive value of SRC-1 for tamoxifen response of recurrent breast cancer. Breast Cancer Res Treat 48(1):87–92PubMedCrossRef

13.

Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS (2011) FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet 43(1):27–33. doi:10.1038/ng.730 PubMedCrossRefPubMedCentral

14.

Giamas G, Filipovic A, Jacob J, Messier W, Zhang H, Yang D, Zhang W, Shifa BA, Photiou A, Tralau-Stewart C, Castellano L, Green AR, Coombes RC, Ellis IO, Ali S, Lenz HJ, Stebbing J (2011) Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer. Nat Med 17(6):715–719. doi:10.1038/nm.2351 PubMedCrossRef

15.

Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ (1997) CDK-independent activation of estrogen receptor by cyclin D1. Cell 88(3):405–415PubMedCrossRef

16.

Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R (2007) A functional genetic approach identifies the PI3 K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12(4):395–402. doi:10.1016/j.ccr.2007.08.030 PubMedCrossRef

17.

Jensen JD, Knoop A, Laenkholm AV, Grauslund M, Jensen MB, Santoni-Rugiu E, Andersson M, Ewertz M (2012) PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. Ann Oncol 23(8):2034–2042. doi:10.1093/annonc/mdr546 PubMedCrossRef

18.

Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, Barretina J, Lin WM, Rameh L, Salmena L, Pandolfi PP, Cantley LC (2009) Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3 K signaling. Cancer Cell 16(2):115–125. doi:10.1016/j.ccr.2009.06.006 PubMedCrossRefPubMedCentral

19.

Balko JM, Cook RS, Vaught DB, Kuba MG, Miller TW, Bhola NE, Sanders ME, Granja-Ingram NM, Smith JJ, Meszoely IM, Salter J, Dowsett M, Stemke-Hale K, Gonzalez-Angulo AM, Mills GB, Pinto JA, Gomez HL, Arteaga CL (2012) Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat Med 18(7):1052–1059. doi:10.1038/nm.2795 PubMedCrossRefPubMedCentral

20.

Gillett C, Fantl V, Smith R, Fisher C, Bartek J, Dickson C, Barnes D, Peters G (1994) Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res 54(7):1812–1817PubMed

21.

Meyerson M, Harlow E (1994) Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol 14(3):2077–2086PubMedPubMedCentral

22.

Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ (1992) Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 71(2):323–334PubMedCrossRef

23.

Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stal O, Sicinski P (2006) Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9(1):23–32. doi:10.1016/j.ccr.2005.12.012 PubMedCrossRef

24.

Ding C, Cantor CR (2003) A high-throughput gene expression analysis technique using competitive PCR and matrix-assisted laser desorption ionization time-of-flight MS. Proc Natl Acad Sci U S A 100(6):3059–3064PubMedCrossRefPubMedCentral

25.

Elvidge GP, Price TS, Glenny L, Ragoussis J (2005) Development and evaluation of real competitive PCR for high-throughput quantitative applications. Anal Biochem 339(2):231–241. doi:10.1016/j.ab.2005.01.040 PubMedCrossRef

26.

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3 (7):RESEARCH0034

27.

Arihiro K, Umemura S, Kurosumi M, Moriya T, Oyama T, Yamashita H, Umekita Y, Komoike Y, Shimizu C, Fukushima H, Kajiwara H, Akiyama F (2007) Comparison of evaluations for hormone receptors in breast carcinoma using two manual and three automated immunohistochemical assays. Am J Clin Pathol 127(3):356–365. doi:10.1309/4D1A04NCDK96WFY7 PubMedCrossRef

28.

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. Mod Pathol 19(7):999–1009. doi:10.1038/modpathol.3800621 PubMedCrossRef

29.

Dawson SJ, Makretsov N, Blows FM, Driver KE, Provenzano E, Le Quesne J, Baglietto L, Severi G, Giles GG, McLean CA, Callagy G, Green AR, Ellis I, Gelmon K, Turashvili G, Leung S, Aparicio S, Huntsman D, Caldas C, Pharoah P (2010) BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer 103(5):668–675. doi:10.1038/sj.bjc.6605736 PubMedCrossRefPubMedCentral

30.

Esteva FJ, Guo H, Zhang S, Santa-Maria C, Stone S, Lanchbury JS, Sahin AA, Hortobagyi GN, Yu D (2010) PTEN, PIK3CA, p-AKT, and p-p70S6 K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am J Pathol 177(4):1647–1656. doi:10.2353/ajpath.2010.090885 PubMedCrossRefPubMedCentral

31.

Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2):117–127PubMedCrossRef

32.

Denkert C, Huober J, Loibl S, Prinzler J, Kronenwett R, Darb-Esfahani S, Brase JC, Solbach C, Mehta K, Fasching PA, Sinn BV, Engels K, Reinisch M, Hansmann ML, Tesch H, von Minckwitz G, Untch M (2013) HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer. Breast Cancer Res 15(1):R11. doi:10.1186/bcr3384 PubMedCrossRefPubMedCentral

33.

Gong Y, Yan K, Lin F, Anderson K, Sotiriou C, Andre F, Holmes FA, Valero V, Booser D, Pippen JE Jr, Vukelja S, Gomez H, Mejia J, Barajas LJ, Hess KR, Sneige N, Hortobagyi GN, Pusztai L, Symmans WF (2007) Determination of oestrogen-receptor status and ERBB2 status of breast carcinoma: a gene-expression profiling study. Lancet Oncol 8(3):203–211. doi:10.1016/S1470-2045(07)70042-6 PubMedCrossRef

34.

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. doi:10.1186/bcr2419 PubMedCrossRefPubMedCentral

35.

Richard S, Finn JPC, Istvan Lang, Katalin Boer, Igor M. Bondarenko, Sergey O. Kulyk, Johannes Ettl, Ravindranath Patel, Tamas Pinter, Marcus Schmidt, Yaroslav V. Shparyk, Anu R. Thummala, Nataliya L. Voytko, Xin Huang, Sindy T. Kim, Sophia S. Randolph, Dennis J. Slamon Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER +/HER2- advanced breast cancer (PALOMA-1; TRIO-18) In: American Association for Cancer Research Annual Meeting, San Diego, 2014. CT101

36.

TCGA (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70. doi:10.1038/nature11412 CrossRef

37.

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. doi:10.1186/bcr2142 PubMedCrossRefPubMedCentral

38.

Witkiewicz AK, Ertel A, McFalls J, Valsecchi ME, Schwartz G, Knudsen ES (2012) RB-pathway disruption is associated with improved response to neoadjuvant chemotherapy in breast cancer. Clin Cancer Res 18(18):5110–5122. doi:10.1158/1078-0432.CCR-12-0903 PubMedCrossRef

39.

Lehn S, Ferno M, Jirstrom K, Ryden L, Landberg G (2011) A non-functional retinoblastoma tumor suppressor (RB) pathway in premenopausal breast cancer is associated with resistance to tamoxifen. Cell Cycle 10(6):956–962PubMedCrossRef

40.

Finn RS, Press MF, Dering J, Arbushites M, Koehler M, Oliva C, Williams LS, Di Leo A (2009) Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer. J Clin Oncol 27(24):3908–3915. doi:10.1200/JCO.2008.18.1925 PubMedCrossRefPubMedCentral

41.

Cheng H, Ballman K, Vassilakopoulou M, Dueck AC, Reinholz MM, Tenner K, Gralow J, Hudis C, Davidson NE, Fountzilas G, McCullough AE, Chen B, Psyrri A, Rimm DL, Perez EA (2014) EGFR expression is associated with decreased benefit from trastuzumab in the NCCTG N9831 (Alliance) trial. Br J Cancer. doi:10.1038/bjc.2014.442

42.

Hoadley KA, Weigman VJ, Fan C, Sawyer LR, He X, Troester MA, Sartor CI, Rieger-House T, Bernard PS, Carey LA, Perou CM (2007) EGFR associated expression profiles vary with breast tumor subtype. BMC Genom 8:258. doi:10.1186/1471-2164-8-258 CrossRef

Title: Transcriptional CCND1 expression as a predictor of poor response to neoadjuvant chemotherapy with trastuzumab in HER2-positive/ER-positive breast cancer
Authors: M. Tanioka
K. Sakai
T. Sudo
T. Sakuma
K. Kajimoto
K. Hirokaga
S. Takao
S. Negoro
H. Minami
K. Nakagawa
K. Nishio
Publication date: 01-10-2014
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2014
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-014-3121-5

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