Lapatinib is a HER1 and HER2 tyrosine kinase inhibitor (TKI) approved in second line treatment of advanced or metastatic breast cancer following progression on trastuzumab-containing therapy. Biomarkers for activity of lapatinib and other TKIs are lacking. Formalin-fixed, paraffin-embedded primary tumor samples were obtained from 189 HER2-positive patients treated with lapatinib plus capecitabine following progression on trastuzumab. The HERmark® Breast Cancer Assay was used to quantify HER2 protein expression. HER3 and p95HER2 protein expression was quantified using the VeraTag® technology. Overall survival (OS) was inversely correlated with HER2 (HR = 1.9/log; P = 0.009) for patients with tumors above the cut-off positivity level by the HERmark assay. OS was significantly shorter for those with above median HER2 levels (HR = 1.7; P = 0.015) and trended shorter for those below the cut-off level of positivity by the HERmark assay (HR = 1.7; P = 0.057) compared to cases with moderate HER2 overexpression. The relationship between HER2 protein expression and OS was best captured with a U-shaped parabolic function (P = 0.004), with the best prognosis at moderate levels of HER2 protein overexpression. In a multivariate model including HER2, increasing p95HER2 expression was associated with longer OS (HR = 0.35/log; P = 0.027). Continuous HER3 did not significantly correlate with OS. Patients with moderately overexpressed HER2 levels and high p95HER2 expression may have best outcomes while receiving lapatinib following progression on trastuzumab. Further study is warranted to explore the predictive utility of quantitative HER2 and p95HER2 in guiding HER2-directed therapies.

Białystok Oncology Center Białystok Poland

Masaryk Memorial Cancer Institute Brno Czech Republic

Medical University of Gdańsk Gdańsk Poland

Medical University of Łódź Łódź Poland

Military Institute of Medicine Warsaw Poland

Monogram Biosciences Integrated Oncology Laboratory Corporation of America Holdings South San Francisco CA USA

National Institute of Oncology Budapest Hungary

Oncology Center Kielce Poland

Oncology Center Zielona Góra Poland

Oncology Institute Kraków Poland

Opole Oncology Center Opole Poland

Regional Hospital Wrocław Poland

Warmia and Masuria Oncology Center Olsztyn Poland

Zobrazit více v PubMed

Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–43. https://doi.org/10.1056/NEJMoa064320. PubMed DOI

Press MF, Finn RS, Cameron D, Di Leo A, Geyer CE, Villalobos IE, Santiago A, Guzman R, Gasparyan A, Ma Y, Danenberg K, Martin AM, Williams L, et al. HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res. 2008;14:7861–70. https://doi.org/10.1158/1078-0432.CCR-08-1056. PubMed DOI

D’Amato V, Raimondo L, Formisano L, Giuliano M, De Placido S, Rosa R, Bianco R. Mechanisms of lapatinib resistance in HER2-driven breast cancer. Cancer Treat Rev. 2015;41:877–83. https://doi.org/10.1016/j.ctrv.2015.08.001. PubMed DOI

Lee CK, Davies L, Gebski VJ, Lord SJ, Di Leo A, Johnston S, Geyer C, Jr, Cameron D, Press MF, Ellis C, Loi S, Marschner I, Simes J, et al. Serum human epidermal growth factor 2 extracellular domain as a predictive biomarker for lapatinib treatment efficacy in patients with advanced breast cancer. J Clin Oncol. 2016;34:936–44. https://doi.org/10.1200/JCO.2015.62.4767. PubMed DOI

Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008;112:533–43. https://doi.org/10.1007/s10549-007-9885-0. PubMed DOI

Scaltriti M, Chandarlapaty S, Prudkin L, Aura C, Jimenez J, Angelini PD, Sanchez G, Guzman M, Parra JL, Ellis C, Gagnon R, Koehler M, Gomez H, et al. Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor. Clin Cancer Res. 2010;16:2688–95. https://doi.org/10.1158/1078-0432.CCR-09-3407. PubMed DOI PMC

Han SW, Cha Y, Paquet A, Huang W, Weidler J, Lie Y, Sherwood T, Bates M, Haddad M, Park IH, Oh DY, Lee KS, Im SA, et al. Correlation of HER2, p95HER2 and HER3 expression and treatment outcome of lapatinib plus capecitabine in her2-positive metastatic breast cancer. PLoS One. 2012;7:e39943. https://doi.org/10.1371/journal.pone.0039943. PubMed DOI PMC

O’Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, Duffy MJ, Crown J, O’Donovan N, Slamon DJ. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther. 2010;9:1489–502. https://doi.org/10.1158/1535-7163.MCT-09-1171. PubMed DOI

Fabi A, Merola R, Ferretti G, Di Benedetto A, Antoniani B, Ercolani C, Nistico C, Papaldo P, Ciccarese M, Sperduti I, Vici P, Marino M, Gori S, et al. Epidermal growth factor receptor gene copy number may predict lapatinib sensitivity in HER2-positive metastatic breast cancer. Expert Opin Pharmacother. 2013;14:699–706. https://doi.org/10.1517/14656566.2013.779672. PubMed DOI

Prat A, Cheang MC, Galvan P, Nuciforo P, Pare L, Adamo B, Munoz M, Viladot M, Press MF, Gagnon R, Ellis C, Johnston S. Prognostic value of intrinsic subtypes in hormone receptor-positive metastatic breast cancer treated with letrozole with or without lapatinib. JAMA Oncol. 2016;2:1287–94. https://doi.org/10.1001/jamaoncol.2016.0922. PubMed DOI

Gori S, Inno A, Rossi V, Turazza M, Fiorio E, Fabi A, Bisagni G, Foglietta J, Santini D, Pavese I, Pellegrino A, Zambelli A, Vici P, et al. Predictive factors of lapatinib and capecitabine activity in patients with HER2-positive, trastuzumab-resistant metastatic breast cancer: results from the Italian retrospective multicenter HERLAPAC study. PLoS One. 2016;11:e0156221. https://doi.org/10.1371/journal.pone.0156221. PubMed DOI PMC

Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, Ejlertsen B, Chia SK, Mansi J, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17:367–77. https://doi.org/10.1016/S1470-2045(15)00551-3. PubMed DOI

Moulder SL, Borges VF, Baetz T, McSpadden T, Fernetich G, Murthy RK, Chavira R, Guthrie K, Barrett E, Chia SK. Phase I study of ONT-380, a HER2 inhibitor, in patients with HER2+-advanced solid tumors, with an expansion cohort in HER2+ metastatic breast cancer (MBC) Clin Cancer Res. 2017 https://doi.org/10.1158/1078-0432.CCR-16-1496. PubMed DOI

Duchnowska R, Wysocki PJ, Korski K, Czartoryska-Arlukowicz B, Niwinska A, Orlikowska M, Radecka B, Studzinski M, Demlova R, Ziolkowska B, Merdalska M, Hajac L, Mysliwiec P, et al. Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients. Oncotarget. 2016;7:550–64. https://doi.org/10.18632/oncotarget.6375. PubMed DOI PMC

Huang W, Reinholz M, Weidler J, Yolanda L, Paquet A, Whitcomb J, Lingle W, Jenkins RB, Chen B, Larson JS, Tan Y, Sherwood T, Bates M, et al. Comparison of central HER2 testing with quantitative total HER2 expression and HER2 homodimer measurements using a novel proximity-based assay. Am J Clin Pathol. 2010;134:303–11. https://doi.org/10.1309/AJCP3BZY4YAFNTRG. PubMed DOI

Yardley DA, Kaufman PA, Huang W, Krekow L, Savin M, Lawler WE, Zrada S, Starr A, Einhorn H, Schwartzberg LS, Adams JW, Lie Y, Paquet AC, et al. Quantitative measurement of HER2 expression in breast cancers: comparison with ‘real-world’ routine HER2 testing in a multicenter Collaborative Biomarker Study and correlation with overall survival. Breast Cancer Res. 2015;17:41. https://doi.org/10.1186/s13058-015-0543-x. PubMed DOI PMC

Nuciforo P, Thyparambil S, Galván P, Vilaro M, Jimenez J, Liao WL, Cecchi F, Blackler A, Press M, Gagnon R, Ellis C, Hembrough T, Johnston S, et al. (2015). Quantitative HER family proteins assessment as prognostic and predictive biomarkers in the EGF30008 clinical trial. San Antonio Breast Cancer Symposium, Abstract P3-07-08.

Baselga J, Lewis Phillips GD, Verma S, Ro J, Huober J, Guardino AE, Samant MK, Olsen S, de Haas SL, Pegram MD. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-positive metastatic breast cancer. Clin Cancer Res. 2016;22:3755–63. https://doi.org/10.1158/1078-0432.CCR-15-2499. PubMed DOI PMC

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82. PubMed

Van Poznak C, Somerfield MR, Bast RC, Cristofanilli M, Goetz MP, Gonzalez-Angulo AM, Hicks DG, Hill EG, Liu MC, Lucas W, Mayer IA, Mennel RG, Symmans WF, et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2015;33:2695–704. https://doi.org/10.1200/JCO.2015.61.1459. PubMed DOI PMC

Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, Di Cosimo S, Matias-Guiu X, Ramon y Cajal S, Arribas J, Baselga J. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628–38. https://doi.org/10.1093/jnci/djk134. PubMed DOI

Lin NU, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, Roche H, Liu MC, Greil R, Ciruelos E, Loibl S, Gori S, Wardley A, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009;15:1452–9. https://doi.org/10.1158/1078-0432.CCR-08-1080. PubMed DOI

Bachelot T, Romieu G, Campone M, Dieras V, Cropet C, Dalenc F, Jimenez M, Le Rhun E, Pierga JY, Goncalves A, Leheurteur M, Domont J, Gutierrez M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14:64–71. https://doi.org/10.1016/S1470-2045(12)70432-1. PubMed DOI

Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437–41. https://doi.org/10.1038/nature05474. PubMed DOI PMC

Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sanchez V, Chakrabarty A, Dave B, Cook RS, Pao W, McKinely E, Manning HC, Chang J, Arteaga CL. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci U S A. 2011;108:5021–6. https://doi.org/10.1073/pnas.1016140108. PubMed DOI PMC

Nishimura R, Toh U, Tanaka M, Saimura M, Okumura Y, Saito T, Tanaka T, Teraoka M, Shimada K, Katayama K, Koga T, Kurashita K, Hasegawa S, et al. Role of HER2-related biomarkers (HER2, p95HER2, HER3, PTEN, and PIK3CA) in the efficacy of lapatinib plus capecitabine in HER2-positive avanced breast cancer refractory to trastuzumab. Oncology. 2017;93:51–61. https://doi.org/10.1159/000468521. PubMed DOI

Lipton A, Goodman L, Leitzel K, Cook J, Sperinde J, Haddad M, Kostler WJ, Huang W, Weidler JM, Ali S, Newton A, Fuchs EM, Paquet A, et al. HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2013;141:43–53. https://doi.org/10.1007/s10549-013-2665-0. PubMed DOI PMC

Sperinde J, Jin X, Banerjee J, Penuel E, Saha A, Diedrich G, Huang W, Leitzel K, Weidler J, Ali SM, Fuchs EM, Singer CF, Kostler WJ, et al. Quantitation of p95HER2 in paraffin sections by using a p95-specific antibody and correlation with outcome in a cohort of trastuzumab-treated breast cancer patients. Clin Cancer Res. 2010;16:4226–35. https://doi.org/10.1158/1078-0432.CCR-10-0410. PubMed DOI

Duchnowska R, Sperinde J, Chenna A, Haddad M, Paquet A, Lie Y, Weidler JM, Huang W, Winslow J, Jankowski T, Czartoryska-Arlukowicz B, Wysocki PJ, Foszczynska-Kloda M, et al. Quantitative measurements of tumoral p95HER2 protein expression in metastatic breast cancer patients treated with trastuzumab: independent validation of the p95HER2 clinical cutoff. Clin Cancer Res. 2014;20:2805–13. https://doi.org/10.1158/1078-0432.CCR-13-2782. PubMed DOI

Pedersen K, Angelini PD, Laos S, Bach-Faig A, Cunningham MP, Ferrer-Ramon C, Luque-Garcia A, Garcia-Castillo J, Parra-Palau JL, Scaltriti M, Ramon y Cajal S, Baselga J, Arribas J. A naturally occurring HER2 carboxy-terminal fragment promotes mammary tumor growth and metastasis. Mol Cell Biol. 2009;29:3319–31. https://doi.org/10.1128/MCB.01803-08. PubMed DOI PMC