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Basic science

2230 - Tumor microenvironment biomarkers as therapeutic strategies for TNBC

Date

10 Sep 2017

Session

Basic science

Presenters

Federico Rojo

Citation

Annals of Oncology (2017) 28 (suppl_5): v595-v604. 10.1093/annonc/mdx391

Authors

F. Rojo1, M. Ruíz-Borrego2, M. Hui3, J.M. Trigo Perez4, A. Cazet3, M.A. Karsdal5, A. Urruticoechea6, S. Antolin7, J.A. García-Saenz8, S. O’toole3, A. Blach9, L. Perez-Ramos10, S. Bezares11, M. Sánchez-Aragó12, R. Caballero13, C.L. Bager5, A. Swarbrick14, M. Martin Jimenez15

Author affiliations

  • 1 Cancer Institute, Hospital Universitario Fundación Jimenez Diaz, GEICAM, CIBERONC-ISCIII, 28040 - Madrid/ES
  • 2 Clinical Oncology, Hospital Virgen del Rocío, Sevilla/ES
  • 3 Translational Breast Cancer Research, Garvan Institute of Medical Research, Darlinghurst, New South Wales/AU
  • 4 Clinical Oncology, Hospital Universitario Virgen de la Victoria, IBIMA, 29010 - Malaga/ES
  • 5 Biomarkers & Research, Nordic Bioscience A/S, 2730 - Herlev/DK
  • 6 Clinical Oncology, Fundación Onkologikoa, Donosti/ES
  • 7 Clinical Oncology, Complejo Hospitalario U A Coruña, Coruña/ES
  • 8 Medical Oncology, Hospital Universitario Clínico San Carlos, Madrid/ES
  • 9 Translational Research, GEICAM, 28703 - San Sebastian de los Reyes/ES
  • 10 Statistics, GEICAM, 28703 - San Sebastian de los Reyes/ES
  • 11 Medical Lead, GEICAM, 28703 - San Sebastian de los Reyes/ES
  • 12 Traslational Research, GEICAM, 28703 - San Sebastian de los Reyes/ES
  • 13 Traslational Research Director, GEICAM, 28703 - San Sebastian de los Reyes/ES
  • 14 Tumour Progression, Garvan Institute of Medical Research, Darlinghurst, New South Wales/AU
  • 15 Medical Oncology, Hospital General Universitario Gregorio Marañón, GEICAM, CIBERONC-ISCIII, 28009 - Madrid/ES
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Resources

Abstract 2230

Background

Patients with triple negative breast cancer (TNBC) comprise a heterogeneous and poor-prognosis subgroup. Biomarkers for targeted therapy development remains a challenge. Progression of TNBC is associated with extracellular matrix (ECM) remodeling and reactivation of the paracrine Hedgehog (Hh) pathway, highlighting the relevance of tumor micronvironment (TME) in tumorigenesis. We investigated whether TME biomarkers could determine clinical response in TNBC patients treated with the Hh pathway inhibitor sonidegib in combination with docetaxel.

Methods

Patients enrolled in GEICAM/2012-12 (EDALINE) trial were included (n = 12). To evaluate Hh pathway activation, the expression of SHH and GLI1 was centrally examined by immunohistochemistry in pre-treatment primary tumors. A Hh Pathway Activation Signature (HPAS) was defined when SHH expression in epithelium and GLI1 in stroma were high (> median). Biomarkers involved in formation and degradation of ECM (C1M, C3M, C4M, C6M, pro-C3, pro-C6, CRPM, Loxl-2 and VCANM) were evaluated by ELISA (Protein Fingerprint™) in sequential plasma samples. ECM signature (ECMS) was defined when C4M and VCANM were high at baseline (> median).

Results

Related to Hh pathway activation, only 10 tumors had IHC results. Three patients had high HPAS, 2 of them experienced a clinical benefit, 1 complete response (CR) and 1 stable disease (SD) lasting 7.3 and 5.5 months, respectively. All patients with low HPAS expression progressed. An additional patient had clinical benefit but the status of Hh pathway activation was unknown. For ECM biomarkers, a maintained reduction was observed in the expression along treatment (C2D1-0.5h, C2D2-25h and C4D1) vs baseline for pro-C3 (12.8, 10.2 and 9.4 vs 16.6, p = 0.05, p = 0.03, p = 0.25, respectively), and pro-C6 (9.2, 7.5 and 8 vs 9.95, p = 0.13, p 

Conclusions

Hh pathway activation and ECM remodeling might be associated with improved benefit to sonidegib in combination with docetaxel in TNBC metastatic patients.

Clinical trial identification

NCT02027376.

Legal entity responsible for the study

GEICAM Spanish Breast Group.

Funding

Australian National Health and Medical Research Council.

Disclosure

M. Hui: Institution conducts research funding by Pfizer. M.A. Karsdal: Employed by Nordic Bioscience in a compensated leadership role and owns interest in the company. A. Urruticoechea: Consulting advisory role in Eisai. Travel accommodation expenses by Roche, Merck and Eisai. S. O’Toole: Honoraria from Bristol Myers. C.L. Bager: Employed by Nordic Bioscience. A. Swarbrick: Institution receives research funding from Novartis Pharmaceuticals. Honoraria from Roche. M. Martin Jimenez: Speaker honoraria and advisory boards of AstraZeneca. All other authors have declared no conflicts of interest.

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