HRAS is a therapeutic target in malignant chemo-resistant adenomyoepithelioma of the breast

Ivan Bièche,Sophie Château-Joubert,Cécile Reyes,Fabien Reyal,Elisabetta Marangoni,André Nicolas,Florence Coussy,Marick Laé,Anne Vincent-Salomon,Sophie Vacher,Rania El-Botty,Caterina Marchio,Elodie Montaudon,David Gentien,Francesco Ricci,Ahmed Dahmani

doi:10.1186/s13045-021-01158-3

Abstract

Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours’ samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.

Highlights

Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential
As HRAS mutations are associated to activation of RAF/MEK/ERK signaling in different cancers [11], we treated the patient-derived xenografts (PDX) HBCx121 by a combination of dabrafenib and trametinib
PDX HBCx-121 responded with stable disease to trametinib, while dabrafenib had no effect on tumor growth (Fig. 1c)

Summary

Introduction

Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. It is generally a benign disease and cases of malignant AME are rare [1]. *Correspondence: elisabetta.marangoni@curie.fr 5 Translational Research Department, Institut Curie, PSL Research University, 26 Rue d’Ulm, 75005 Paris, France Full list of author information is available at the end of the article (ER) and progesterone receptor (PR) [1]. These findings are concordant with those previously reported [7, 8] and underline the co-occurrence of two cancer driver genes in a fraction of malignant AMEs. From one of the four malignant AMEs patients (T13), whose clinical history is summarized, we could generate two PDX, HBCx-120 and HBCx-121, established from the engraftment of the breast tumour and the axillary lymph node metastasis, respectively.

Results

Conclusion