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Clinical Studies

No evidence of disease versus residual disease in long-term responders to first-line HER2-targeted therapy for metastatic breast cancer

British Journal of Cancer volume 126, pages 881–888 (2022)Cite this article

Subjects

Abstract

Background

Long-term response to HER2-targeted therapies is infrequent in metastatic breast cancer (MBC). We evaluated clinical characteristics of HER2-positive MBC patients with no evidence of disease (NED) vs residual disease (RES) experiencing long-term response to first-line HER2-targeted therapy.

Methods

Patients receiving first-line chemotherapy-trastuzumab (CT) or taxane-trastuzumab-pertuzumab (THP) with response duration ≥2-fold higher than in phase II/III trials (CT [18.2 months]; THP [40.4 months]) were included. Clinical characteristics and radiographic review for NED or RES was evaluated by Cox-regression (hazard ratio; HR) or Kaplan–Meier (log-rank). Characteristics associated with NED were evaluated by logistic regression (Odds; OR).

Results

From 01/2005-01/2016, N = 103 (4.6%) patients were identified. In multivariate analyses, NED (N = 46) showed improved progression-free (PFS) and overall survival (OS) [p < 0.001] versus RES (N = 57), with high 5-year PFS/OS for NED (93.2%/97.4%) relative to RES (10.6%/61.3%). Premenopausal status (p = 0.006), de-novo metastases (p = 0.002), and no palliative radiotherapy (p = 0.01) were associated with NED. Overall, 6/7 (85.7%) patients with NED were alive and disease-free after discontinuing HER2 treatment (≥1 year) versus 1/17 (5.9%) with RES.

Conclusions

Long-term responders with NED have better survival compared to RES. Premenopausal status and de novo metastatic disease are associated with NED. Prospective studies of HER2 therapy discontinuation with NED in MBC are warranted.

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Fig. 1
Fig. 2
Fig. 3: Swimmer’s plot of survival for patients receiving first-line HER2 therapies.

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Data availability

The data that support the findings of this study are available upon request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.

References

  1. Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389:1195–205. https://doi.org/10.1016/S0140-6736(16)32616-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32:3744–52. https://doi.org/10.1200/JCO.2014.55.5730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N. Engl J Med. 2015;372:724–34. https://doi.org/10.1056/NEJMoa1413513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, et al. Tucatinib, trastuzumab, and capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2019; https://doi.org/10.1056/nejmoa1914609.

  5. Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol: Off J Am Soc Clin Oncol. 2020;38:3138–49. https://doi.org/10.1200/JCO.20.00147.

    Article  CAS  Google Scholar 

  6. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl J Med. 2020;382:610–21. https://doi.org/10.1056/NEJMoa1914510.

    Article  CAS  PubMed  Google Scholar 

  7. Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, et al. End-of-study analysis from the phase III, randomized, double-blind, placebo (Pla)-controlled CLEOPATRA study of first-line (1L) pertuzumab (P), trastuzumab (H), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC). J Clin Oncol. 2019;37:1020–1020. https://doi.org/10.1200/JCO.2019.37.15_suppl.1020.

    Article  Google Scholar 

  8. Banerji U, van Herpen CML, Saura C, Thistlethwaite F, Lord S, Moreno V, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019;20:1124–35. https://doi.org/10.1016/S1470-2045(19)30328-6.

    Article  CAS  PubMed  Google Scholar 

  9. Butterbaugh ST, Patel R, Romond EH, Mathew A. Trastuzumab use in patients with durable complete response in HER2-amplified metastatic breast cancer: to continue or not to continue. Ann Oncol. 2017;28:3098–9. https://doi.org/10.1093/annonc/mdx532.

    Article  CAS  PubMed  Google Scholar 

  10. Wong Y, Raghavendra AS, Hatzis C, Irizarry JP, Vega T, Horowitz N, et al. Long‐term survival of de novo stage IV human epidermal growth receptor 2 (HER2) positive breast cancers treated with HER2‐targeted therapy. Oncologist. 2019;24:313–8. https://doi.org/10.1634/theoncologist.2018-0213.

    Article  CAS  PubMed  Google Scholar 

  11. Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, et al. LBA1 Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. Ann Oncol. 2021;32. https://doi.org/10.1016/j.annonc.2021.08.2087.

  12. Datta J, Fracol M, McMillan MT, Berk E, Xu S, Goodman N, et al. Association of depressed anti-HER2 T-helper type 1 response with recurrence in patients with completely treated HER2-positive breast cancer: role for immune monitoring. JAMA Oncol. 2016;2:242–6. https://doi.org/10.1001/jamaoncol.2015.5482.

    Article  PubMed  Google Scholar 

  13. Datta J, Berk E, Xu S, Fitzpatrick E, Rosemblit C, Lowenfeld L, et al. Anti-HER2 CD4+ T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer. Breast Cancer Res. 2015;17:71 https://doi.org/10.1186/s13058-015-0584-1.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Griguolo G, Pascual T, Dieci MV, Guarneri V, Prat A. Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer. J Immunother Cancer. 2019;7:90 https://doi.org/10.1186/s40425-019-0548-6.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 2019;20:371–82. https://doi.org/10.1016/S1470-2045(18)30812-X.

    Article  CAS  PubMed  Google Scholar 

  16. Emens LA, Esteva FJ, Beresford M, Saura C, De Laurentiis M, Kim SB, et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020;21:1283–95. https://doi.org/10.1016/S1470-2045(20)30465-4.

    Article  CAS  PubMed  Google Scholar 

  17. Witzel I, Müller V, Abenhardt W, Kaufmann M, Schoenegg W, Schneeweis A, et al. Long-term tumor remission under trastuzumab treatment for HER2 positive metastatic breast cancer—results from the HER-OS patient registry. BMC Cancer. 2014;14:806 https://doi.org/10.1186/1471-2407-14-806.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yardley DA, Tripathy D, Brufsky AM, Rugo HS, Kaufman PA, Mayer M, et al. Long-term survivor characteristics in HER2-positive metastatic breast cancer from registHER. Br J Cancer. 2014;110:2756–64. https://doi.org/10.1038/bjc.2014.174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Moilanen T, Mustanoja S, Karihtala P, Koivunen JP. Retrospective analysis of HER2 therapy interruption in patients responding to the treatment in metastatic HER2+ breast cancer. ESMO Open. 2017;2:e000202 https://doi.org/10.1136/esmoopen-2017-000202.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Gullo G, Zuradelli M, Sclafani F, Santoro A, Crown J. Durable complete response following chemotherapy and trastuzumab for metastatic HER2-positive breast cancer. Ann Oncol. 2012;23:2204–5. https://doi.org/10.1093/annonc/mds221.

    Article  CAS  PubMed  Google Scholar 

  21. Niikura N, Shimomura A, Fukatsu Y, Sawaki M, Ogiya R, Yasojima H, et al. Durable complete response in HER2-positive breast cancer: a multicenter retrospective analysis. Breast Cancer Res Treat. 2018;167:81–87. https://doi.org/10.1007/s10549-017-4489-9.

    Article  PubMed  Google Scholar 

  22. Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554:189–94. https://doi.org/10.1038/nature25475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Altundag K. Duration of trastuzumab in HER2-positive metastatic breast cancer after complete remission: still debatable issue? Breast Cancer Res Treat. 2018;167:815–815. https://doi.org/10.1007/s10549-017-4536-6.

    Article  PubMed  Google Scholar 

  24. Viel E, Arbion F, Barbe C, Bougnoux P. Prolonged complete response after treatment withdrawal in HER2-overexpressed, hormone receptor-negative breast cancer with liver metastases: the prospect of disappearance of an incurable disease. BMC Cancer. 2014;14:690 https://doi.org/10.1186/1471-2407-14-690.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lambertini M, Vaz-Luis I. Is HER2-positive metastatic breast cancer still an incurable disease? Lancet Oncol. 2020;21:471–2. https://doi.org/10.1016/S1470-2045(20)30058-9.

    Article  PubMed  Google Scholar 

  26. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl J Med. 2012;367:1783–91. https://doi.org/10.1056/NEJMoa1209124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chan A, Martin M, Untch M, Gil MG, Guillem-Porta V, Wojtukiewicz M, et al. Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial. Br J Cancer. 2006;95:788–93. https://doi.org/10.1038/sj.bjc.6603351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Urruticoechea A, Rizwanullah M, Im SA, Ruiz ACS, Láng I, Tomasello G, et al. Randomized phase III trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therap. J Clin Oncol. 2017;35:3030–8. https://doi.org/10.1200/JCO.2016.70.6267.

    Article  CAS  PubMed  Google Scholar 

  29. Schaller G, Fuchs I, Gonsch T, Weber J, Kleine-Tebbe A, Klare P, et al. Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2–overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes. J Clin Oncol. 2007;25:3246–50. https://doi.org/10.1200/JCO.2006.09.6826.

    Article  CAS  PubMed  Google Scholar 

  30. Murthy P, Kidwell KM, Schott AF, Merajver SD, Griggs JJ, Smerage JD, Van Poznak CH, Wicha MS, Hayes DF, Henry NL. Clinical predictors of long-term survival in HER2-positive metastatic breast cancer. Breast cancer Res Treat. 2016;155:589–95. https://doi.org/10.1007/s10549-016-3705-3.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Printz C. NCI launches exceptional responders initiative: researchers will attempt to identify why some patients respond to treatment so much better than others. Cancer. 2015;121:803–4. https://doi.org/10.1002/cncr.29311.

    Article  PubMed  Google Scholar 

  32. Cescon DW, Bratman SV, Chan SM, Siu LL. Circulating tumor DNA and liquid biopsy in oncology. Nat Cancer. 2020;1:276–90. https://doi.org/10.1038/s43018-020-0043-5.

    Article  CAS  PubMed  Google Scholar 

  33. Magbanua MJM, Swigart LB, Wu HT, Hirst GL, Yau C, Wolf DM, et al. Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival. Ann Oncol. 2021;32:229–39. https://doi.org/10.1016/j.annonc.2020.11.007.

    Article  CAS  PubMed  Google Scholar 

  34. Tokudome N, Hayes DF. Analysis of circulating tumor DNA to monitor metastatic breast cancer. Breast Dis: A Year Book Q. 2013;24:350–2. https://doi.org/10.1016/j.breastdis.2013.10.034.

    Article  Google Scholar 

  35. Guan X, Liu B, Niu Y, Dong X, Zhu X, Li C, et al. Longitudinal HER2 amplification tracked in circulating tumor DNA for therapeutic effect monitoring and prognostic evaluation in patients with breast cancer. Breast. 2020;49:261–6. https://doi.org/10.1016/j.breast.2019.12.010.

    Article  PubMed  Google Scholar 

  36. Ma F, Zhu W, Guan Y, Yang L, Xia X, Chen S, et al. ctDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy. Oncotarget. 2016;7:66020–31. https://doi.org/10.18632/oncotarget.11791.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Gradishar WJ, Anderson BO, Abraham J, Aft R, Agnese D, Allison KH, et al. Breast cancer, version 3.2020, NCCN Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020;18. https://doi.org/10.6004/jnccn.2020.0016.

  38. Perez EA, Cortés J, Gonzalez-Angulo AM, Bartlett JMS. HER2 testing: current status and future directions. Cancer Treat Rev. 2014;40:276–84. https://doi.org/10.1016/j.ctrv.2013.09.001.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Princess Margaret Cancer Centre and Cancer Care Alberta would like to acknowledge the patients and families for their contribution to this research. This study was presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, USA, in June 2019.

Funding

No funding was procured for this study.

Author information

Authors and Affiliations

  1. Department of Medical Oncology and Hematology, St Michael’s Hospital, Toronto, ON, Canada

    Zachary Veitch

  2. Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada

    Zachary Veitch, Philippe L. Bedard & David W. Cescon

  3. Medical Oncology Department, Institute of Oncology Ljubljana, Ljubljana, Slovenia

    Domen Ribnikar

  4. Cancer Care Alberta, Alberta Health Services, Calgary, AB, Canada

    Derek Tilley

  5. Department of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada

    Patricia A. Tang & Sasha Lupichuk

  6. Department of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada

    Karen King

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Contributions

Conceptualisation—ZWV, PAT, DR, KK, SL and DC. Data curation—ZWV, SL, KK and DR. Formal analyses—ZWV and DT. Funding acquisition—None. Investigation—ZWV and DR, Methodology—ZWV, PAT and SL. Project administration—ZWV, DWC and PLB. Resources—ZWV, DT and DWC. Software—ZWV and DT. Supervision—SL and DWC. Validation—Not applicable. Visualisation—ZWV. Writing—Original draft—ZWV. Writing—Review and editing—ZWV, DR, DT, PAT, KK, PLB, SL and DWC.

Corresponding author

Correspondence to Zachary Veitch.

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Ethics approval and consent to participate

This study was approved by the Princess Margaret Cancer Centre Research Ethics Board (NCT03740503) and the Health and Research Ethics Board of Alberta (Cancer Committee).

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Not applicable.

Competing interests

ZWV has received honoraria from Pfizer, Exact Sciences, Knight Pharmaceuticals, and Novartis. DWC reports consultancy and advisory fees from AstraZeneca, Exact Sciences, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer, and Roche; research funding to their institution from GlaxoSmithKline, Inivata, Merck, Pfizer and Roche; is a member of a trial steering committee for Merck; and holds a patent (US62/675,228) for methods of treating cancers characterised by a high expression level of spindle and kinetochore associated complex subunit 3 (ska3) gene. PLB has received research funding from Bristol-Myers Squibb, Sanofi, AstraZeneca, Genentech/Roche, SERVIER, GlaxoSmithKline, Novartis, SignalChem, PTC Therapeutics, Nektar, Merck, Seattle Genetics, Mersana, Immunomedics, Eli-Lilly, Zymeworks, and VelosBio. Uncompensated advisory for Lilly, Seagen, Merck, Genentech/Roche, Bristol-Myers Squibb, and Gilead. PAT has honoraria from Teva, Eisai, Pfizer, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca and Roche. No conflicts of interest: The following authors have declared no conflicts of interest: DR, DT, KK and SL.

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Veitch, Z., Ribnikar, D., Tilley, D. et al. No evidence of disease versus residual disease in long-term responders to first-line HER2-targeted therapy for metastatic breast cancer. Br J Cancer 126, 881–888 (2022). https://doi.org/10.1038/s41416-021-01676-4

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