Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer
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Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy.
Patients and methods
Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR).
Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006).
PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.
KeywordsPIK3CA mutations PTEN levels HER2-positive breast cancer pCR Lapatinib Trastuzumab
This work was supported in part by NCI grants P50CA58183 and P50CA186784 (SPORE), P30CA125123, P30CA008748, and R01CA72038, Department of Defense grants W81XWH-17-1-0579 and W81XWH-17-1-0580, as well as grants from the Komen Foundation for the Cure, the Avon Foundation, the Breast Cancer Research Foundation, the Cancer Prevention & Research Institute of Texas CPRIT RP 140102, the Conquer Cancer Foundation—Gianni Bonadonna Breast Cancer Research Fellowship and the Translational Breast Cancer Research Consortium. None of the funding agencies had any role in the design, analysis, or reporting of analyses. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
MR, CA, AC, BW, JSR-F, CKO, RS: Study design, data collection, data analysis, data interpretation, and writing. FP, FCG, KAB, SH, TW, SGH, MML: Study design, data analysis, data interpretation, and writing. IAM, AF, RN, MPG, JCG, ACP, SAWF, CG: Study design, data collection, data interpretation, and writing. IEK, ACW: Study design, data interpretation, and writing.
Compliance with ethical standards
Conflict of interest
Mothaffar F. Rimawi: Research grant from GlaxoSmithKline (to Institution), Consulting with Genentech. Andres Forero: Research grants from GlaxoSmithKline and Genentech (to Institution). Ian E. Krop: Consulting: Genentech/Roche. Research grant from Genentech/Roche (to Institution). Antonio C. Wolff: Research grant from Genentech (to Institution). Carmine De Angelis, Alejandro Contreras, Fresia Pareja, Felipe C. Geyer, Kathleen A. Burke, Sabrina Herrera, Tao Wang, Ingrid A Mayer, Rita Nanda, Matthew P. Goetz, Jenny C. Chang, Anne C. Pavlick, Suzanne A. W. Fuqua, Carolina Gutierrez, Susan G. Hilsenbeck, Marilyn M. Li, Britta Weigelt, Jorge S. Reis-Filho, C. Kent Osborne, Rachel Schiff have conclude nothing to disclose.
- 8.Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X et al (2011) Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers–role of estrogen receptor and HER2 reactivation. Breast cancer Res 13(6):R121. doi: 10.1186/bcr3067 CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Rimawi MF, Wiechmann LS, Wang YC, Huang C, Migliaccio I, Wu MF et al (2011) Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu-overexpressing breast tumor xenografts. Clin Cancer Res 17(6):1351–1361. doi: 10.1158/1078-0432.CCR-10-1905 CrossRefPubMedGoogle Scholar
- 12.Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA et al (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 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC et al (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 CrossRefPubMedGoogle Scholar
- 14.Llombart-Cussac A, Cortes J, Pare L, Galvan P, Bermejo B, Martinez N et al (2017) HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol 18(4):545–554. doi: 10.1016/S1470-2045(17)30021-9 CrossRefPubMedGoogle Scholar
- 15.Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C et al (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 CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R et al (2013) Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24(9):2278–2284. doi: 10.1093/annonc/mdt182 CrossRefPubMedGoogle Scholar
- 18.Fujita T, Doihara H, Kawasaki K, Takabatake D, Takahashi H, Washio K et al (2006) PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer 94(2):247–252. doi: 10.1038/sj.bjc.6602926 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Esteva FJ, Guo H, Zhang S, Santa-Maria C, Stone S, Lanchbury JS et al (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 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Scaltriti M, Eichhorn PJ, Cortes J, Prudkin L, Aura C, Jimenez J et al (2011) Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc Natl Acad Sci USA 108(9):3761–3766. doi: 10.1073/pnas.1014835108 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Gallardo A, Lerma E, Escuin D, Tibau A, Munoz J, Ojeda B et al (2012) Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. Br J Cancer 106(8):1367–1373. doi: 10.1038/bjc.2012.85 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Dave B, Migliaccio I, Gutierrez MC, Wu MF, Chamness GC, Wong H et al (2011) Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol 29(2):166–173. doi: 10.1200/JCO.2009.27.7814 CrossRefPubMedGoogle Scholar
- 25.Nuciforo PG, Aura C, Holmes E, Prudkin L, Jimenez J, Martinez P et al (2015) Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status. Ann Oncol 26(7):1494–1500. doi: 10.1093/annonc/mdv175 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Perez EA, Dueck AC, McCullough AE, Chen B, Geiger XJ, Jenkins RB et al (2013) Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. J Clin Oncol 31(17):2115–2122. doi: 10.1200/JCO.2012.42.2642 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Stern HM, Gardner H, Burzykowski T, Elatre W, O’Brien C, Lackner MR et al (2015) PTEN loss is associated with worse outcome in HER2-amplified breast cancer patients but is not associated with trastuzumab resistance. Clin Cancer Res 21(9):2065–2074. doi: 10.1158/1078-0432.CCR-14-2993 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Fu X, Creighton CJ, Biswal NC, Kumar V, Shea M, Herrera S et al (2014) Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase. Breast Cancer Res 16(5):430. doi: 10.1186/s13058-014-0430-x CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ et al (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. doi: 10.1200/JCO.2006.09.2775 CrossRefPubMedGoogle Scholar
- 30.Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med 134(6):907–922. doi: 10.1043/1543-2165-134.6.907 PubMedPubMedCentralGoogle Scholar
- 31.Piscuoglio S, Ng CK, Murray M, Burke KA, Edelweiss M, Geyer FC et al (2016) Massively parallel sequencing of phyllodes tumours of the breast reveals actionable mutations, and TERT promoter hotspot mutations and TERT gene amplification as likely drivers of progression. J Pathol 238(4):508–518. doi: 10.1002/path.4672 CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Society HGV 2016 Sequence variant nomenclature version 15.11. http://varnomen.hgvs.org/
- 40.Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G et al (2016) Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. J Clin Oncol 34(10):1034–1042. doi: 10.1200/JCO.2015.62.1797 CrossRefPubMedGoogle Scholar
- 44.Loi S, Michiels S, Lambrechts D, Salgado R, Sirtaine N, Fumagalli D et al (2012) Tumor PIK3CA mutations, lymphocyte infiltration, and recurrence-free survival (RFS) in early breast cancer (BC): results from the FinHER trial. J Clin Oncol 30(Suppl.):507Google Scholar
- 47.Majewski IJ, Nuciforo P, Mittempergher L, Bosma AJ, Eidtmann H, Holmes E et al (2015) PIK3CA Mutations Are Associated With Decreased Benefit to Neoadjuvant Human Epidermal Growth Factor Receptor 2-Targeted Therapies in Breast Cancer. J Clin Oncol. doi: 10.1200/JCO.2014.55.2158 PubMedPubMedCentralGoogle Scholar
- 48.Bianchini G, Kiermaier A, Bianchi GV, Im YH, Pienkowski T, Liu MC et al (2017) Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer. Breast Cancer Res 19(1):16. doi: 10.1186/s13058-017-0806-9 CrossRefPubMedPubMedCentralGoogle Scholar
- 49.Loibl S, von Minckwitz G, Schneeweiss A, Paepke S, Lehmann A, Rezai M et al (2014) PIK3CA Mutations Are Associated With Lower Rates of Pathologic Complete Response to Anti-Human Epidermal Growth Factor Receptor 2 (HER2) Therapy in Primary HER2-Overexpressing Breast Cancer. J Clin Oncol. doi: 10.1200/JCO.2014.55.7876 Google Scholar
- 50.Guarneri V, Generali DG, Frassoldati A, Artioli F, Boni C, Cavanna L et al (2014) Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. J Clin Oncol 32(10):1050–1057. doi: 10.1200/JCO.2013.51.4737 CrossRefPubMedGoogle Scholar