Pathway activity profiling can predict neoadjuvant endocrine therapy response in HR+ HER2- postmenopausal early stage breast cancer

Breast Cancer Research, vol. 28

Abstract

AIM: To improve patient selection for neoadjuvant endocrine therapy (NET), signal transduction pathway profiles of estrogen receptor (ER)-, androgen receptor (AR), were studied and compared to standard immunohistochemistry (IHC) in postmenopausal patients with HR+ (IHC ER ≥ 50%, progesterone receptor any), HER2- breast cancer of the NEOLBC trial (NCT03283384). METHODS: After two weeks of NET with letrozole, patients with Ki67 (Ki67-2 W) ≥ 1% IHC were randomized to receive letrozole + ribociclib or standard chemotherapy until surgery, while patients with Ki67-2 W < 1% continued NET (letrozole monotherapy). Baseline, two week- and resection FFPE samples of 82 patients were analyzed using mRNA-based OncoSIGNal profiling test, providing the pathway activity score (PAS). RESULTS: Despite samples being ER-IHC ≥ 50%, the ER-PAS varied over a range of 32–78 (scale from 0 to 100) with 20% of the patients showing low ER-PAS (32–45; similar to triple negative breast cancer tissue). At 2 weeks, 89% (73/82) of the patients showed a decreased ER-PAS (11.6 ± 8.6) compared to baseline (p < 0.001), whereas ER-IHC remained unchanged. Patients with complete response (RECIST1.1) appeared to have a higher ER-PAS at baseline compared to those with stable disease (p = 0.03), ROC analysis confirmed ER-PAS at baseline as an acceptable predictive factor for MRI response (AUC ≥ 0.7). Lastly, baseline and 2-week pathway activity profiling could identify targetable escape mechanisms for NET non-responders, which could improve personalized treatment strategies. CONCLUSION: ER IHC+ does not correlate to ER-PAS and ER-PAS is a more dynamic marker that appears to reflect variable NET response more accurately than IHC.

Authors 19

1. N. de Gruil Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center, Leiden, The Netherlands

2. A. F. de Groot Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center, Leiden, The Netherlands

3. Yvonne J.W. Wesseling-Rozendaal
   Affiliation as printed

   InnoSIGN B.V., Eindhoven, The Netherlands

4. D. Keizer
   Affiliation as printed

   InnoSIGN B.V., Eindhoven, The Netherlands

5. C.S. Koekenbier Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center, Leiden, The Netherlands

6. S. Vermeer
   Affiliation as printed

   InnoSIGN B.V., Eindhoven, The Netherlands

7. D. Cohen Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center, Leiden, The Netherlands

8. JB Heijns

   Amphia Ziekenhuis

   Affiliation as printed

   Department of Medical Oncology, Amphia, Breda, The Netherlands

9. C. M. P. W. Mandigers

   Canisius-Wilhelmina Ziekenhuis

   Affiliation as printed

   Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands

10. A.J. van de Wouw

    VieCuri Medisch Centrum

    Affiliation as printed

    Department of Medical Oncology, VieCuri Medical Center, Venlo, The Netherlands

11. M. Cloos-van Balen

    Groene Hart Ziekenhuis

    Affiliation as printed

    Department of Medical Oncology, Groene Hart Hospital, Gouda, The Netherlands

12. J. A. Ropela
    Affiliation as printed

    Department of Medical Oncology, St. Jansdal, Harderwijk, The Netherlands

13. HM Oosterkamp

    Medisch Centrum Haaglanden · Stichting Haaglanden Medisch Centrum

    Affiliation as printed

    Department of Medical Oncology, Haaglanden Medical Center, The Hague, The Netherlands

14. M. L. van Bekkum

    Reinier de Graaf Hospital

    Affiliation as printed

    Department of Medical Oncology, Reinier de Graaf Gasthuis, Delft, The Netherlands

15. D. Houtsma

    Haga Hospital

    Affiliation as printed

    Department of Medical Oncology, HAGA Hospital, The Hague, The Netherlands

16. E. den Biezen
    Affiliation as printed

    InnoSIGN B.V., Eindhoven, The Netherlands

17. G.-J. Liefers Aachen

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center, Leiden, The Netherlands

18. S.C. Linn

    The Netherlands Cancer Institute · University Medical Center Utrecht

    Affiliation as printed

    Antoni van Leeuwenhoek Hospital, Amsterdam, and University Medical Center Utrecht, Utrecht, The Netherlands

19. Judith R. Kroep corresponding Aachen

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center, Leiden, The Netherlands. j.r.kroep@lumc.nl