Radiological complete remission in HER2-positive metastatic breast cancer patients: what to do with trastuzumab?

  • T. G. Steenbruggen
  • N. I. Bouwer
  • C. H. Smorenburg
  • H. N. Rier
  • A. Jager
  • K. Beelen
  • A. J. ten Tije
  • P. C. de Jong
  • J. C. Drooger
  • C. Holterhues
  • J. J. E. M. Kitzen
  • M. -D. Levin
  • G. S. SonkeEmail author
Clinical trial



Patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab may experience durable tumor response for many years. It is unknown if patients with durable radiological complete remission (rCR) can discontinue trastuzumab. We analyzed clinical characteristics associated with rCR and overall survival (OS) in a historic cohort of patients with HER2-positive MBC and studied the effect of stopping trastuzumab in case of rCR.


We included patients with HER2-positive MBC treated with first or second-line trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Data were collected from medical records. We used multivariable regression models to identify independent prognostic factors for rCR and OS. Time-to-progression after achieving rCR for patients who continued and stopped trastuzumab, and breast cancer-specific survival were also evaluated.


We identified 717 patients with a median age of 53 years at MBC diagnosis. The median follow-up was 109 months (IQR 72-148). The strongest factor associated with OS was achievement of rCR, adjusted hazard ratio 0.27 (95% CI 0.18–0.40). RCR was observed in 72 patients (10%). The ten-year OS estimate for patients who achieved rCR was 52 versus 7% for patients who did not achieve rCR. Thirty patients with rCR discontinued trastuzumab, of whom 20 (67%) are alive in ongoing remission after 78 months of median follow-up since rCR. Of forty patients (58%) who continued trastuzumab since rCR, 13 (33%) are in ongoing remission after 68 months of median follow-up. Median time-to-progression in the latter group was 14 months.


Achieving rCR is the strongest predictor for improved survival in patients with HER2-positive MBC. Trastuzumab may be discontinued in selected patients with ongoing rCR. Further research is required to identify patients who have achieved rCR and in whom trastuzumab may safely be discontinued.


HER2-positive Metastatic breast cancer Long-term survival Radiological complete remission Trastuzumab 



We thank Dr. Ritse Mann and Dr. Claudette E. Loo for their valuable comments on radiological imaging. We thank Caroline Pauwels-Heemskerk for her assistance with identifying patients in the Netherlands Cancer Institute’s tumor registry, and Jorine Rigterink for her assistance with collecting data in the Netherlands Cancer Institute.

Author contributions

Study concepts and design: TGS, CHS, GSS. Data acquisition: all authors. Quality control of data and algorithms: TGS. Data analysis and interpretation: TGS, NIB, CHS, AJ, ML, GSS. Statistical analyses: TGS. Manuscript preparation: TGS. Manuscript editing: TGS, NIB, CHS, AJ, ML, GSS. Manuscript review and approval: all authors.


This project was funded by Stichting A Sister’s Hope and Stichting [Z]aan de Wandel.

Compliance with ethical standards

Conflict of interest

TGS received funding from Memidis Pharma outside the current project. GSS has received institutional research funding from AstraZeneca, Merck, Novartis, and Roche. NIB, CHS, HNvR, AJ, KB, AJtT, PCdJ, JCD, CH, JK, and MDL have no disclosures. All authors have declared no conflict of interest.

Ethical approval

The Review Board of each participating center approved this study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

No formal consent was required.

Supplementary material

10549_2019_5427_MOESM1_ESM.docx (40 kb)
Supplementary material 1 (DOCX 41 kb)


  1. 1.
    Cardoso F, Senkus E, Costa A et al (2018) 4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4). Ann Oncol Off J Eur Soc Med Oncol 29:1634–1657. CrossRefGoogle Scholar
  2. 2.
    Sundquist M, Brudin L, Tejler G (2017) Improved survival in metastatic breast cancer 1985-2016. Breast 31:46–50. CrossRefGoogle Scholar
  3. 3.
    Weide R, Feiten S, Friesenhahn V et al (2014) Metastatic breast cancer: prolongation of survival in routine care is restricted to hormone-receptor- and Her2-positive tumors. Springerplus 3:535. CrossRefGoogle Scholar
  4. 4.
    Dawood S, Broglio K, Buzdar AU et al (2010) Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol 28:92–98. CrossRefGoogle Scholar
  5. 5.
    Mendes D, Alves C, Afonso N et al (2015) The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer—a systematic review. Breast Cancer Res 17:140. CrossRefGoogle Scholar
  6. 6.
    Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792. CrossRefGoogle Scholar
  7. 7.
    Gullo G, Zuradelli M, Sclafani F et al (2012) Durable complete response following chemotherapy and trastuzumab for metastatic HER2-positive breast cancer. Ann Oncol 23:2204–2208CrossRefGoogle Scholar
  8. 8.
    Baselga J, Manikhas A, Cortes J et al (2014) Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer. Ann Oncol Off J Eur Soc Med Oncol 25:592–598. CrossRefGoogle Scholar
  9. 9.
    Andersson M, Lidbrink E, Bjerre K et al (2011) Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol 29:264–271. CrossRefGoogle Scholar
  10. 10.
    Valero V, Forbes J, Pegram MD et al (2011) Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeu. J Clin Oncol 29:149–156. CrossRefGoogle Scholar
  11. 11.
    Swain SM, Baselga J, Kim S-B et al (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724–734. CrossRefGoogle Scholar
  12. 12.
    Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743. CrossRefGoogle Scholar
  13. 13.
    Verma S, Miles D, Gianni L et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791. CrossRefGoogle Scholar
  14. 14.
    Dzimitrowicz H, Berger M, Vargo C et al (2016) T-DM1 activity in metastatic human epidermal growth factor receptor 2-positive breast cancers that received prior therapy with trastuzumab and pertuzumab. J Clin Oncol 34:3511–3517. CrossRefGoogle Scholar
  15. 15.
    Yardley D, Tripathy D, Brufsky AM et al (2014) Long-term survivor characteristics in HER2 positive MBC from registHER. Br J Cancer 110:2756–2764CrossRefGoogle Scholar
  16. 16.
    Spano J-P, Beuzeboc P, Coeffic D et al (2015) Long term HER2+ metastatic breast cancer survivors treated by trastuzumab: results from the French cohort study LHORA. Breast 24:376–383CrossRefGoogle Scholar
  17. 17.
    Murthy P, Kidwell KM, Schott AF et al (2016) Clinical predictors of long-term survival in HER2-positive metastatic breast cancer. Breast Cancer Res Treat 155:589–595. CrossRefGoogle Scholar
  18. 18.
    Bishop A, Ensor J, Moulder S et al (2015) Prognosis for patients with metastatic breast cancer who achieve NED after systemic or local therapy. Cancer 121:4324–4332CrossRefGoogle Scholar
  19. 19.
    Rier HN, Levin M-D, van Rosmalen J et al (2017) First-line palliative HER2-targeted therapy in HER2-positive metastatic breast cancer is less effective after previous adjuvant trastuzumab-based therapy. Oncologist 22:901–909. CrossRefGoogle Scholar
  20. 20.
    Moilanen T, Mustanoja S, Karihtala P, Koivunen JP (2017) Retrospective analysis of HER2 therapy interruption in patients responding to the treatment in metastatic HER2+ breast cancer. ESMO Open 2:e000202. CrossRefGoogle Scholar
  21. 21.
    Murthy RK, Varma A, Mishra P et al (2014) Effect of adjuvant/neoadjuvant trastuzumab on clinical outcomes in patients with HER2-positive metastatic breast cancer. Cancer 120:1932–1938. CrossRefGoogle Scholar
  22. 22.
    Pagani O, Senkus E, Wood W et al (2010) International guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured? J Natl Cancer Inst 102:456–463. CrossRefGoogle Scholar
  23. 23.
    Witzel I, Müller V, Abenhardt W et al (2014) Long-term tumor remission under trastuzumab treatment for HER2 positive metastatic breast cancer—results from the HER-OS patient registry. BMC Cancer 14:1–7. CrossRefGoogle Scholar
  24. 24.
    Wong Y, Raghavendra AS, Hatzis C et al (2018) Long-term survival of de Novo Stage IV human epidermal growth receptor 2 (HER2) positive breast cancers treated with HER2-targeted therapy. Oncologist. Google Scholar
  25. 25.
    Bringolf L, Pestalozzi B, Fink D, Dedes K (2016) Exploring prognostic factors for HER2-positive metastatic breast cancer: a retrospective cohort study in a major Swiss hospital. Swiss Med Wkly 146:w14393. Google Scholar
  26. 26.
    Haq R, Gulasingam P (2016) Duration of trastuzumab in patients with HER2-positive metastatic breast cancer in prolonged remission. Curr Oncol 23:91. CrossRefGoogle Scholar
  27. 27.
    Niikura N, Shimomura A, Fukatsu Y et al (2018) Durable complete response in HER2-positive breast cancer: a multicenter retrospective analysis. Breast Cancer Res Treat 167:81–87. CrossRefGoogle Scholar
  28. 28.
    Hammond MEH (2011) ASCO-CAP guidelines for breast predictive factor testing: an update. Appl Immunohistochem Mol Morphol 19:499–500. CrossRefGoogle Scholar
  29. 29.
  30. 30.
    Senkus E, Kyriakides S, Ohno S et al (2015) Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 26(Suppl 5):v8–v30. CrossRefGoogle Scholar
  31. 31.
    Hudis CA, Barlow WE, Costantino JP et al (2007) Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol 25:2127–2132. CrossRefGoogle Scholar
  32. 32.
    Robert C, Ribas A, Hamid O et al (2018) Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J Clin Oncol 36:1668–1674. CrossRefGoogle Scholar
  33. 33.
    Harano K, Lei X, Gonzalez-Angulo AM, Murthy RK, Valero V, Mittendorf EA, Ueno NT, Hortobagyi GN, Chavez-MacGregor M (2016) Clinicopathological and surgical factors associated with long-term survival in patients with HER2-positive metastatic breast cancer. Breast Cancer Res Treat 159:367–374CrossRefGoogle Scholar
  34. 34.
    Rossi S, Basso M, Strippoli A et al (2015) Hormone receptor status and HER2 expression in primary breast cancer compared with synchronous axillary metastases or recurrent metastatic disease. Clin Breast Cancer 15:307–312. CrossRefGoogle Scholar
  35. 35.
    Palma DA, Salama JK, Lo SS et al (2014) The oligometastatic state—separating truth from wishful thinking. Nat Rev Clin Oncol 11:549–557CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • T. G. Steenbruggen
    • 1
  • N. I. Bouwer
    • 2
  • C. H. Smorenburg
    • 1
  • H. N. Rier
    • 2
  • A. Jager
    • 3
  • K. Beelen
    • 4
  • A. J. ten Tije
    • 5
  • P. C. de Jong
    • 6
  • J. C. Drooger
    • 7
  • C. Holterhues
    • 8
  • J. J. E. M. Kitzen
    • 2
  • M. -D. Levin
    • 2
  • G. S. Sonke
    • 1
    Email author
  1. 1.Department of Medical OncologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.Department of Internal MedicineAlbert Schweitzer HospitalDordrechtThe Netherlands
  3. 3.Department of Medical OncologyErasmus MC Cancer InstituteRotterdamThe Netherlands
  4. 4.Department of Internal MedicineReinier de Graaf HospitalDelftThe Netherlands
  5. 5.Department of Internal MedicineAmphia HospitalBredaThe Netherlands
  6. 6.Department of Medical OncologySint Antonius HospitalUtrechtThe Netherlands
  7. 7.Department of Medical OncologyIkazia HospitalRotterdamThe Netherlands
  8. 8.Department of Internal MedicineHaga HospitalThe HagueThe Netherlands

Personalised recommendations