nach oben

Erschienen in:

07.11.2017 | Clinical trial

Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer

verfasst von: Mothaffar F. Rimawi, Carmine De Angelis, Alejandro Contreras, Fresia Pareja, Felipe C. Geyer, Kathleen A. Burke, Sabrina Herrera, Tao Wang, Ingrid A. Mayer, Andres Forero, Rita Nanda, Matthew P. Goetz, Jenny C. Chang, Ian E. Krop, Antonio C. Wolff, 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

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 3/2018

Einloggen, um Zugang zu erhalten

Abstract

Purpose

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).

Results

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).

Conclusion

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.

Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707–712CrossRefPubMed

Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC et al (1998) erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90(18):1346–1360CrossRefPubMed

Zardavas D, Fouad TM, Piccart M (2015) Optimal adjuvant treatment for patients with HER2-positive breast cancer in 2015. Breast 24(Suppl 2):S143–S148. doi:10.1016/j.breast.2015.07.034 CrossRefPubMed

Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7(7):505–516CrossRefPubMed

Rimawi MF, Schiff R, Osborne CK (2015) Targeting HER2 for the treatment of breast cancer. Annu Rev Med 66:111–128. doi:10.1146/annurev-med-042513-015127 CrossRefPubMed

Rexer BN, Arteaga CL (2012) Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog 17(1):1–16CrossRefPubMedPubMedCentral

Ghosh R, Narasanna A, Wang SE, Liu S, Chakrabarty A, Balko JM et al (2011) Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers. Cancer Res 71(5):1871–1882. doi:10.1158/0008-5472.CAN-10-1872 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z et al (2003) Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 95(2):142–153CrossRefPubMed

10.

Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwani L et al (2007) Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst 99(9):694–705. doi:10.1093/jnci/djk151 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

17.

Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K et al (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12(4):395–402. doi:10.1016/j.ccr.200708030 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

22.

Brady SW, Zhang J, Seok D, Wang H, Yu D (2014) Enhanced PI3K p110alpha signaling confers acquired lapatinib resistance that can be effectively reversed by a p110alpha-selective PI3K inhibitor. Mol Cancer Ther 13(1):60–70. doi:10.1158/1535-7163.MCT-13-0518 CrossRefPubMed

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 CrossRefPubMed

24.

Xia W, Husain I, Liu L, Bacus S, Saini S, Spohn J et al (2007) Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ErbB2-overexpressing breast cancers. Can Res 67(3):1170–1175. doi:10.1158/0008-5472.CAN-06-2101 CrossRef

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 PubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

32.

Chang F, Li MM (2013) Clinical application of amplicon-based next-generation sequencing in cancer. Cancer genet 206(12):413–419. doi:10.1016/j.cancergen.2013.10.003 CrossRefPubMed

33.

Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G et al (2011) Integrative genomics viewer. Nat Biotechnol 29(1):24–26. doi:10.1038/nbt.1754 CrossRefPubMedPubMedCentral

34.

Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C et al (2013) Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 31(3):213–219. doi:10.1038/nbt.2514 CrossRefPubMedPubMedCentral

35.

Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L et al (2012) VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 22(3):568–576. doi:10.1101/gr.129684.111 CrossRefPubMedPubMedCentral

36.

Saunders CT, Wong WS, Swamy S, Becq J, Murray LJ, Cheetham RK (2012) Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics 28(14):1811–1817. doi:10.1093/bioinformatics/bts271 CrossRefPubMed

37.

Eberle CA, Piscuoglio S, Rakha EA, Ng CK, Geyer FC, Edelweiss M et al (2016) Infiltrating epitheliosis of the breast: characterization of histological features, immunophenotype and genomic profile. Histopathology 68(7):1030–1039. doi:10.1111/his.12897 CrossRefPubMedPubMedCentral

38.

Society HGV 2016 Sequence variant nomenclature version 15.11. http://varnomen.hgvs.org/

39.

Alimonti A, Carracedo A, Clohessy JG, Trotman LC, Nardella C, Egia A et al (2010) Subtle variations in Pten dose determine cancer susceptibility. Nat Genet 42(5):454–458. doi:10.1038/ng.556 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

41.

von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G et al (2017) Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. doi:10.1056/NEJMoa1703643

42.

Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK et al (2015) Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372(2):134–141. doi:10.1056/NEJMoa1406281 CrossRefPubMedPubMedCentral

43.

Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2):117–127. doi:10.1016/j.ccr.2004.06.022 CrossRefPubMed

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.):507

45.

Loibl S, Darb-Esfahani S, Huober J, Klimowicz A, Furlanetto J, Lederer B et al (2016) Integrated analysis of PTEN and p4EBP1 protein expression as predictors for pCR in HER2-positive breast cancer. Clin Cancer Res 22(11):2675–2683. doi:10.1158/1078-0432.CCR-15-0965 CrossRefPubMed

46.

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

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 PubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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

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 CrossRefPubMed

Titel: Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer
verfasst von: Mothaffar F. Rimawi
Carmine De Angelis
Alejandro Contreras
Fresia Pareja
Felipe C. Geyer
Kathleen A. Burke
Sabrina Herrera
Tao Wang
Ingrid A. Mayer
Andres Forero
Rita Nanda
Matthew P. Goetz
Jenny C. Chang
Ian E. Krop
Antonio C. Wolff
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
Publikationsdatum: 07.11.2017
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 3/2018
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-017-4533-9

Neu im Fachgebiet Onkologie

25.04.2024 | Nierenkarzinom | Nachrichten

Springer Medizin

Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer

Abstract

Purpose

Patients and methods

Results

Conclusion

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie

Springer Medizin

Abstract

Purpose

Patients and methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2018

BRCA1 deficiency is a recurrent event in early-onset triple-negative breast cancer: a comprehensive analysis of germline mutations and somatic promoter methylation

CD56+ immune cell infiltration and MICA are decreased in breast lobules with fibrocystic changes

Impact of microinvasion on breast cancer mortality in women with ductal carcinoma in situ

Safety of fertility preservation in breast cancer patients in a register-based matched cohort study

Efficacy and safety in older patient subsets in studies of endocrine monotherapy versus combination therapy in patients with HR+/HER2− advanced breast cancer: a review

The value of embedding: integrated palliative care for patients with metastatic breast cancer

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie