CFAH Seeking out predictive biomarkers to FGFR inhibitors in molecularly-selected metastatic breast cancer – VHIO – Vall d'Hebron Institute of Oncology

Seeking out predictive biomarkers to FGFR inhibitors in molecularly-selected metastatic breast cancer

  • Over recent years, the development of CDK4/6 inhibitors for the more effective treatment of breast cancer has represented a significant advancement. Unfortunately, patients ultimately acquire resistance to these therapies, calling for new therapeutic strategies.
  • Different mechanisms of resistance to these agents have been identified including the amplification of the fibroblast growth factor receptor (FGFR) pathway, which is recurrent in metastatic breast cancer and also a driver of resistance to endocrine therapy.
  • Novel agents including FGFR inhibitors are being developed to improve patients’ outcomes and predicting response to these therapies is paramount. Results from a study led by VHIO’s Violeta Serra propose the measurement of FGFR1-4 mRNA levels as a biomarker of response in molecularly-selected breast cancer.
  • Recently published in Clinical Cancer Research*, results from patient-derived xenografts (PDXs) and breast cancer patient samples support the prospective validation of this approach in luminal CDK4/6 inhibitor-resistant and triple negative breast cancer patients without targeted therapeutic options.

Barcelona, October 27, 2021. The amplification of the fibroblast growth receptor (FGFR) pathway is one of the most frequent molecular mutations in breast cancer. Between 10 and 15% estrogen receptor-positive (ER +) and 4% triple negative breast cancers (TNBC) present  this particular alteration, which is associated with resistance to endocrine therapy (ET) and the current array of CDK 4/6 inhibitors (CDK4/6i).  Aimed at improving outcomes for these patients, novel agents including multi-tyrosine kinase inhibitors (MTKI) and FGFR inhibitors (FGFRi) that hone in on FGFR amplifications are being developed as potential therapeutic strategies against metastatic breast cancer (mBC).

“Seeking out predictive biomarkers of response in order to identify those patients who could benefit most from these new treatments represents an unmet clinical need,” said Violeta Serra, Principal Investigator of VHIO’s Experimental Therapeutics Group, and corresponding author of this present research article*.

Carried out in collaboration with researchers from several other VHIO groups, also counting on the expertise of co-corresponding author Jordi Rodon, an Associate Investigator of our Early Clinical Drug Development Group, and an Associate Professor, The University of Texas MD Anderson Cancer Center (Houston TX, USA), the investigators studied mRNA levels as a predictive biomarker of response to FGFRi in patient-derived xenografts (PDXs) and breast cancer patient samples.

Predicting sensitivity to FGFRi: a particular challenge 

While FGFR amplification is the most frequent molecular alteration in breast cancer, its value as a predictor of sensitivity to FGFR inhibitors remains unclear.  Indeed, although gain/amplification of gene copy number might be associated with an oncogenic-driver state, not all tumors harboring copy number alterations present FGFR mRNA or protein overexpression.

“Our results show that high FGFR mRNA levels measured by nCounter technology, as opposed to DNA copy number, is associated with selective pan-FGFRi response in vivo,” noted Mònica Sánchez-Guixé, a Post-Doctoral Fellow of Violeta Serra’s Group, and first author of this study, which was also co-authored by colleagues at Barcelona’s August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Bellvitge Biomedical Research Institute (IDIBELL), Hospital Clínic Barcelona, as well as the Memorial Sloan Kettering Cancer Center – MSKCC (New York, USA).

The investigators also sought to evaluate the anti-tumor activity of both in the PDXs. In their search for baseline biomarkers, they analyzed changes in the proliferation rate and vascularization patterns.

“We studied the differential mode of action of MTKI versus FGFRi in order to establish whether MTKI achieve greater efficacy than FGFRi due to their dual blockade of FGFR and pro-angiogenic kinases,” explained Violeta Serra.

Treatment with MTKI showed higher response rates than with FGFRi (86% vs. 53%), irrespective of the FGFR1-4 mRNA levels. FGFR-addicted PDXs showed an antiproliferative response to either family of inhibitors, and PDXs exclusively sensitive to MTKI exhibited an additional anti-angiogenic response. Consistently, clinical benefit of MTKI was not associated with high FGFR1-4 mRNA levels, and was observed in patients previously treated with anti-angiogenic therapies.

“Our preclinical results point to the feasibility of refined patient selection guided by FGFR1-4 mRNA levels for treatment with single-agent FGFR inhibitors. Prospective validation in luminal CDK4/6 inhibitor-resistant and triple negative breast cancer patients without targeted therapeutic options, is warranted,” concluded Violeta.

Reference:

*Sánchez-Guixé M, Hierro C, Jiménez J, Viaplana C, Villacampa G, Monelli E, Brasó-Maristany F, Ogbah Z, Parés M, Guzmán M, Grueso J, Rodriguez O, Oliveira M, Azaro A, Garralda E, Tabernero J, Casanovas O, Scaltriti M, Prat A, Dienstmann R, Nuciforo P, Saura C, Graupera M, Vivancos A, Rodon J, Serra V. High FGFR1-4 mRNA expression levels correlate with response to selective FGFR inhibitors in breast cancer. Clin Cancer Res. 2021 Sep 30:clincanres.CCR-21-1810-A.2021. doi: 10.1158/1078-0432.CCR-21-1810. Epub ahead of print. PMID: 34593528.

 

27/10/2021|