The better understanding of the signaling pathways involved in cancer has led to the use of targeted therapies, such as everolimus (E), a mammalian target of rapamycin (mTOR) inhibitor and palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in the treatment of metastatic breast cancer (mBC). However, treatment response is variable, and resistance occurs systematically. We hypothesised that the combination of gene sequencing and protein expression analysis could help, in a patient, to identify resistance mechanisms occurring on a specified treatment as well as to determine potential further treatments.
We studied paired-biopsies performed in a 69-year-old woman patient with mBC who achieved a durable (16 months) partial response to E-exemestane association. Biopsy 1 was performed before E initiation and biopsy 2 at the progression on E. Analyses were realised with OncoSTRAT&GO™, from OncoDNA company, which combines sequencing of oncogenic genes panel and expression analysis of proteins that could be targeted by current antitumoral agents.
Biopsy 1 revealed PIK3CA(E542K) gene mutation and a high expression of phospho 4EBP1, an effector of mTOR, reflecting an excessive activation of the mTOR pathway that explains the E sensitivity. Biopsies 1 and 2 showed a high expression of phospho-retinoblastoma (pRb), reflecting a continuous cell cycle activation by CDK4/6. Palbociclib was thus initiated in association with letrozole at the progression on E and resulted in a rapid and long-duration (17 months) partial response. In the paired biopsies, the tyrosine kinase receptor cMET was not detected on biopsy 1, but was highly expressed in biopsy 2, suggesting that cMET could play a role in the development of resistance to E. In this context, we are currently treating our patient with cabozantinib (cMET inhibitor). Response profile will be further specified.
These gene and protein expressions reflect correctly the efficacy of targeted therapies this patient received. PIK3CA mutation was associated with E sensitivity and pRb with impressive response to palbociclib. cMET could play a role in the development of resistance to E and its inhibition should be evaluated in mBC.
Clinical trial identification
Legal entity responsible for the study
Centre Hospitalier de Jolimont.
Has not received any funding.
All authors have declared no conflicts of interest.