TCHL – a phase II neo-adjuvant study assessing TCH (docetaxel, carboplatin and trastuzumab) and TCHL (docetaxel, carboplatin, trastuzumab and lapatinib) in HER-2 positive breast cancer patients: a 5-year follow-up with serum biomarker analysis

Authors

  • John Crown Department of Medical Oncology, St Vincent’s University Hospital, Dublin, Ireland; Life Sciences Institute, Dublin City University, Dublin, Ireland
  • Alex J. Eustace Life Sciences Institute, Dublin City University, Dublin, Ireland; School of Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland https://orcid.org/0000-0002-4092-1360
  • Denis M. Collins School of Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland; Cancer Biotherapeutics Research Group, School of Biotechnology, Dublin City University, Dublin, Ireland
  • Maccon Keane Department of Medical Oncology, Galway University Hospital, Ireland
  • Linda Coate Department of Medical Oncology, University Hospital Limerick, Ireland
  • John Kennedy Department of Medical Oncology, St James’s Hospital, Dublin, Ireland
  • Seamus O'Reilly Department of Medical Oncology, Cork University Hospital, Ireland
  • Catherine Kelly Department of Medical Oncology, Mater Hospital, Dublin, Ireland
  • Miriam O'Connor Department of Medical Oncology, Waterford Regional Hospital, Ireland
  • Michael Martin Department of Medical Oncology, Sligo University Hospital, Ireland
  • Conleth Murphy Department of Medical Oncology, Bons Secours Hospital, Cork, Ireland
  • Karen Duffy Department of Medical Oncology, Letterkenny University Hospital, Donegal, Ireland
  • Janice Walshe Department of Medical Oncology, St Vincent’s University Hospital, Dublin, Ireland
  • Giuseppe Gullo Department of Medical Oncology, St Vincent’s University Hospital, Dublin, Ireland
  • Thamir Mahgoub Department of Medical Oncology, University Hospital Limerick, Ireland
  • Alberto Alvarez-Iglesias HRB- Clinical Research Facility, Galway, Ireland
  • Imelda Parker Cancer Trials Ireland/ICORG, Dublin, Ireland
  • Vicky Donachie Cancer Trials Ireland/ICORG, Dublin, Ireland
  • Ausra Teiserskiene Cancer Trials Ireland/ICORG, Dublin, Ireland
  • Stephen F. Madden Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland
  • Brian Moulton Clinical Oncology Development Europe, Dublin, Ireland
  • Norma O'Donovan School of Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland
  • Bryan T. Hennessy Department of Medical Oncology/ICORG/Cancer Trials Ireland, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland

DOI:

https://doi.org/10.2340/1651-226X.2025.43143

Keywords:

HER2-positive breast cancer, neoadjuvant therapy, Trastuzumab, lapatinib, tyrosine kinase inhibitors

Abstract

Background: The docetaxel (T), carboplatin (C) and trastuzumab (H) regimen has been used in the (neo-) adjuvant treatment of HER2+ early stage breast cancer (ESBC). Lapatinib (L) a small molecule HER2 antagonist produces clinical responses following H failure.

Methods: We randomly assigned 88 patients with stages Ic–III HER2+ESBC to receive neoadjuvant TCH, TCL or TCHL followed by surgery and 1 year of H. The primary endpoint was pathological complete response (pCR). Secondary objectives were overall and disease-free survival (OS, DFS).

Results: The TCL arm was closed following demonstration of inferiority of L in another trial. The pCR rates for TCH and TCHL were 52.8 and 51.6 (p = 1.0). At a median 4.8 years follow-up, TCHL patients had a significantly superior DFS; however, OS was similar. Prophylactic loperamide reduced the frequency of diarrhoea. Serum biomarker analysis identified a link between high tumour T-cell levels and high red blood cell, haematocrit, and haemoglobin following commencement of therapy.

Interpretation: The study did not meet its primary endpoint of superior pCR. TCHL produced a significant improvement in DFS. Our study and others suggest a possible role for L in neoadjuvant therapy of HER2+ ESBC.

Clinical Trial Registration: NCT01485926.

Downloads

Download data is not yet available.

References

Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321:288–300.

https://doi.org/10.1001/JAMA.2018.19323 DOI: https://doi.org/10.1001/jama.2018.19323

Riggio AI, Varley KE, Welm AL. The lingering mysteries of metastatic recurrence in breast cancer. Br J Cancer. 2020;124:13–26.

https://doi.org/10.1038/s41416-020-01161-4 DOI: https://doi.org/10.1038/s41416-020-01161-4

Hassan MSU, Ansari J, Spooner D, Hussain SA. Chemotherapy for breast cancer (review). Oncol Rep. 2010;24:1121–31. DOI: https://doi.org/10.3892/or_00000963

https://doi.org/10.3892/OR_00000963/HTML

Agostinetto E, Gligorov J, Piccart M. Systemic therapy for early-stage breast cancer: learning from the past to build the future. Nat Rev Clin Oncol. 2022;19:763–74.

https://doi.org/10.1038/s41571-022-00687-1 DOI: https://doi.org/10.1038/s41571-022-00687-1

Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2+ early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633–40.

https://doi.org/10.1016/S0140-6736(11)61847-3 DOI: https://doi.org/10.1016/S0140-6736(11)61847-3

Guarneri V, Frassoldati A, Bottini A, Cagossi K, Bisagni G, Sarti S, et al. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2–positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol. 2012;30:1989–95.

https://doi.org/10.1200/JCO.2011.39.0823 DOI: https://doi.org/10.1200/JCO.2011.39.0823

Elster N, Collins DM, Toomey S, Crown J, Eustace AJ, Hennessy BT. HER2-family signalling mechanisms, clinical implications and targeting in breast cancer. Breast Cancer Res Treat. 2015;149:5–15.

https://doi.org/10.1007/s10549-014-3250-x DOI: https://doi.org/10.1007/s10549-014-3250-x

Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2+ breast cancer. N Engl J Med. 2011;365:1273–83.

https://doi.org/10.1056/NEJMOA0910383 DOI: https://doi.org/10.1056/NEJMoa0910383

Thompson AM, Moulder-Thompson SL. Neoadjuvant treatment of breast cancer. Ann Oncol. 2012;23(Suppl. 10):x231–6.

https://doi.org/10.1093/ANNONC/MDS324 DOI: https://doi.org/10.1093/annonc/mds324

Davey MG, Browne F, Miller N, Lowery AJ, Kerin MJ. Pathological complete response as a surrogate to improved survival in human epidermal growth factor receptor-2-positive breast cancer: systematic review and meta-analysis. BJS Open. 2022;6:zrac028.

https://doi.org/10.1093/BJSOPEN/ZRAC028 DOI: https://doi.org/10.1093/bjsopen/zrac028

Hurvitz SA, Martin M, Symmans F, Jung KH, Huang C-S, Thompson AM, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2+ breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018;19:115–26.

https://doi.org/10.1016/S1470-2045(17)30716-7 DOI: https://doi.org/10.1016/S1470-2045(17)30716-7

Hurvitz SA, Hegg R, Chung WP, Im SA, Jacot W, Ganju V, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2+ metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401:105–17.

https://doi.org/10.1016/S0140-6736(22)02420-5 DOI: https://doi.org/10.1016/S0140-6736(22)02420-5

von Minckwitz G, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2+ breast cancer. N Engl J Med. 2019;380:617–28. DOI: https://doi.org/10.1056/NEJMoa1814017

https://doi.org/10.1056/NEJMOA1814017/SUPPL_FILE/NEJMOA1814017_DATA-SHARING.PDF

Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2+ advanced breast cancer. N Engl J Med. 2006;355:2733–43.

https://doi.org/10.1056/NEJMoa064320 DOI: https://doi.org/10.1056/NEJMoa064320

Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:1630–9.

https://doi.org/10.1158/0008-5472.CAN-05-1182 DOI: https://doi.org/10.1158/0008-5472.CAN-05-1182

O’Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, et al. 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 DOI: https://doi.org/10.1158/1535-7163.MCT-09-1171

O’Donovan N, Byrne AT, O’Connor AE, McGee S, Gallagher WM, Crown J. Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells. Invest New Drugs. 2011;29:752–9.

https://doi.org/10.1007/S10637-010-9415-5 DOI: https://doi.org/10.1007/s10637-010-9415-5

Crown J, Kennedy MJ, Tresca P, Marty M, Espie M, Burris HA, et al. Optimally tolerated dose of lapatinib in combination with docetaxel plus trastuzumab in first-line treatment of HER2+ metastatic breast cancer. Ann Oncol. 2013;24:2005–11.

https://doi.org/10.1093/ANNONC/MDT222 DOI: https://doi.org/10.1093/annonc/mdt222

Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, et al. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC CTG MA.31. J Clin Oncol. 2015;33:1574–83.

https://doi.org/10.1200/JCO.2014.56.9590 DOI: https://doi.org/10.1200/JCO.2014.56.9590

Eustace AJ, Madden SF, Fay J, Collins DM, Kay EW, Sheehan KM, et al. The role of infiltrating lymphocytes in the neo-adjuvant treatment of women with HER2+ breast cancer. Breast Cancer Res Treat. 2021;187:635–45. DOI: https://doi.org/10.1007/s10549-021-06244-1

https://doi.org/10.1007/S10549-021-06244-1/FIGURES/5

Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7(1):16878.

https://doi.org/10.1038/s41598-017-17204-5 DOI: https://doi.org/10.1038/s41598-017-17204-5

von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2+ early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15:747–56.

https://doi.org/10.1016/S1470-2045(14)70160-3 DOI: https://doi.org/10.1016/S1470-2045(14)70160-3

Robidoux A, Tang G, Rastogi P, Geyer CE, Azar CA, Atkins JN, et al. Lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1183–92.

https://doi.org/10.1016/S1470-2045(13)70411-X DOI: https://doi.org/10.1016/S1470-2045(13)70411-X

Hurvitz SA, Caswell-Jin JL, McNamara KL, Zoeller JJ, Bean GR, Dichmann R, et al. Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2+ breast cancer (TRIO-US B07). Nat Commun. 2020;11(1):5824.

https://doi.org/10.1038/s41467-020-19494-2 DOI: https://doi.org/10.1038/s41467-020-19494-2

Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, et al. Survival, pathologic response, and genomics in CALGB 40601 (alliance), a neoadjuvant phase III trial of paclitaxel-trastuzumab with or without lapatinib in HER2+ breast cancer. J Clin Oncol. 2020;38:4184.

https://doi.org/10.1200/JCO.20.01276 DOI: https://doi.org/10.1200/JCO.20.01276

Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012;13:135–44.

https://doi.org/10.1016/S1470-2045(11)70397-7 DOI: https://doi.org/10.1016/S1470-2045(11)70397-7

Guarneri V, Griguolo G, Miglietta F, Conte PF, Dieci MV, Girardi F. Survival after neoadjuvant therapy with trastuzumab–lapatinib and chemotherapy in patients with HER2+ early breast cancer: a meta-analysis of randomized trials. ESMO Open. 2022;7:100433.

https://doi.org/10.1016/J.ESMOOP.2022.100433 DOI: https://doi.org/10.1016/j.esmoop.2022.100433

Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28:803–14.

https://doi.org/10.1038/ONC.2008.432 DOI: https://doi.org/10.1038/onc.2008.432

Collins DM, Madden SF, Gaynor N, AlSultan D, Le Gal M, Eustace AJ, et al. Effects of HER family-targeting tyrosine kinase inhibitors on antibody-dependent cell-mediated cytotoxicity in HER2-expressing breast cancer. Clin Cancer Res. 2021;27:807–18.

https://doi.org/10.1158/1078-0432.CCR-20-2007 DOI: https://doi.org/10.1158/1078-0432.CCR-20-2007

Gullo G, Walsh N, Fennelly D, Bose R, Walshe J, Tryfonopoulos D, et al. Impact of timing of trastuzumab initiation on long-term outcome of patients with early-stage HER2+ breast cancer: the ‘one thousand HER2 patients’ project. Br J Cancer. 2018;119:374–80.

https://doi.org/10.1038/S41416-018-0114-X DOI: https://doi.org/10.1038/s41416-018-0114-x

Crown JP, Burris HA, Boyle F, Jones S, Koehler M, Newstat BO, et al. Pooled analysis of diarrhea events in patients with cancer treated with lapatinib. Breast Cancer Res Treat. 2008;112:317–25.

https://doi.org/10.1007/S10549-007-9860-9 DOI: https://doi.org/10.1007/s10549-007-9860-9

Chatsiproios D. Breast care safety profile and clinical recommendations for the use of lapatinib. Breast Care. 2010;5:16–21.

https://doi.org/10.1159/000285776 DOI: https://doi.org/10.1159/000285776

Gaynor N, Blanco A, Madden SF, Moran B, Fletcher JM, Kaukonen D, et al. Alterations in immune cell phenotype and cytotoxic capacity in HER2+ breast cancer patients receiving HER2-targeted neo-adjuvant therapy. Br J Cancer. 2023;129:1022–31.

https://doi.org/10.1038/S41416-023-02375-Y DOI: https://doi.org/10.1038/s41416-023-02375-y

Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst. 1999;91:1616–34.

https://doi.org/10.1093/JNCI/91.19.1616 DOI: https://doi.org/10.1093/jnci/91.19.1616

Vuillefroy de Silly R, Dietrich PY, Walker PR. Hypoxia and antitumor CD8+ T cells: an incompatible alliance? Oncoimmunology. 2016;5:e1232236.

https://doi.org/10.1080/2162402X.2016.1232236 DOI: https://doi.org/10.1080/2162402X.2016.1232236

Ohta A. Oxygen-dependent regulation of immune checkpoint mechanisms. Int Immunol. 2018;30:335–43.

https://doi.org/10.1093/INTIMM/DXY038 DOI: https://doi.org/10.1093/intimm/dxy038

Lee CL, Tsai CH, Yeh DC, Lin CS, Li YF, Tzeng HE. Hemoglobin level trajectories in the early treatment period are related with survival outcomes in patients with breast cancer. Oncotarget. 2017;8:1569–79.

https://doi.org/10.18632/ONCOTARGET.13679 DOI: https://doi.org/10.18632/oncotarget.13679

Bottini A, Berruti A, Brizzi MP, Bersiga A, Generali D, Allevi G, et al. Pretreatment haemoglobin levels significantly predict the tumour response to primary chemotherapy in human breast cancer. Br J Cancer. 2003;89:977–82.

https://doi.org/10.1038/SJ.BJC.6601216 DOI: https://doi.org/10.1038/sj.bjc.6601216

Zhu Q, Tannenbaum S, Kurtzman SH, DeFusco P, Ricci A, Vavadi H, et al. Identifying an early treatment window for predicting breast cancer response to neoadjuvant chemotherapy using immunohistopathology and hemoglobin parameters. Breast Cancer Res. 2018;20:56.

https://doi.org/10.1186/S13058-018-0975-1 DOI: https://doi.org/10.1186/s13058-018-0975-1

Xu W, Jiang X, Guan C, Gu M. The prognostic and predictive value of tumor infiltrating Macrophage and neutrophil in patient with clear cell renal cell carcinoma: tumor infiltrating lymphocytes in renal cell carcinoma. Medicine. 2020;99:e23181.

https://doi.org/10.1097/MD.0000000000023181 DOI: https://doi.org/10.1097/MD.0000000000023181

Yang N, Han X, Yu J, Shu W, Qiu F, Han J. Hemoglobin, albumin, lymphocyte, and platelet score and neutrophil-to-lymphocyte ratio are novel significant prognostic factors for patients with small-cell lung cancer undergoing chemotherapy. J Cancer Res Ther. 2020;16:1134–9.

https://doi.org/10.4103/JCRT.JCRT_1066_19 DOI: https://doi.org/10.4103/jcrt.JCRT_1066_19

Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2+ breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17:791–800.

https://doi.org/10.1016/S1470-2045(16)00163-7 DOI: https://doi.org/10.1016/S1470-2045(16)00163-7

Attard CL, Pepper AN, Brown ST, Thompson MF, Thuresson PO, Yunger S, et al. Cost-effectiveness analysis of neoadjuvant pertuzumab and trastuzumab therapy for locally advanced, inflammatory, or early HER2+ breast cancer in Canada. J Med Econ. 2015;18:173–88.

https://doi.org/10.3111/13696998.2014.979938 DOI: https://doi.org/10.3111/13696998.2014.979938

Garrison LP, Babigumira J, Tournier C, Goertz HP, Lubinga SJ, Perez EA. Cost-effectiveness analysis of pertuzumab with trastuzumab and chemotherapy compared to trastuzumab and chemotherapy in the adjuvant treatment of HER2+ breast cancer in the United States. Value Health. 2019;22:408–15.

https://doi.org/10.1016/J.JVAL.2018.11.014 DOI: https://doi.org/10.1016/j.jval.2018.11.014

Augusto Guevara-Cuellar C, Parody-Rúa E, Paula Rengifo-Mosquera M, Conde-Crespo MDM, Nuñez-Castro JM. Cost-effectiveness analysis of pertuzumab plus trastuzumab and docetaxel compared with trastuzumab and docetaxel in the adjuvant treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer in Colombia. Value Health Reg Issues. 2022:32:109–18.

https://doi.org/10.1016/j.vhri.2022.08.002 DOI: https://doi.org/10.1016/j.vhri.2022.08.002

Downloads

Additional Files

Published

2025-06-05

How to Cite

Crown, J., Eustace, A. J., Collins, D. M., Keane, M., Coate, L., Kennedy, J., … Hennessy, B. T. (2025). TCHL – a phase II neo-adjuvant study assessing TCH (docetaxel, carboplatin and trastuzumab) and TCHL (docetaxel, carboplatin, trastuzumab and lapatinib) in HER-2 positive breast cancer patients: a 5-year follow-up with serum biomarker analysis. Acta Oncologica, 64, 751–760. https://doi.org/10.2340/1651-226X.2025.43143

Issue

Vol. 64 (2025): Acta Oncologica

Section

Original article

Categories

License

Copyright (c) 2025 John Crown, Alex J. Eustace, Denis M. Collins, Maccon Keane, Linda Coate, John Kennedy, Seamus O'Reilly, Catherine Kelly, Miriam O'Connor, Michael Martin, Conleth Murphy, Karen Duffy, Janice Walshe, Giuseppe Gullo, Thamir Mahgoub, Alberto Alvarez-Iglesias, Imelda Parker, Vicky Donachie, Ausra Teiserskiene, Stephen F. Madden, Brian Moulton, Norma O'Donovan, Bryan T. Hennessy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.