TY - JOUR
T1 - High FGFR1–4 mRNA Expression Levels Correlate with Response to Selective FGFR Inhibitors in Breast Cancer
AU - Sánchez-Guixé, Mònica
AU - Hierro, Cinta
AU - Jiménez, José
AU - Viaplana, Cristina
AU - Villacampa, Guillermo
AU - Monelli, Erika
AU - Brasó-Maristany, Fara
AU - Ogbah, Zighereda
AU - Parés, Mireia
AU - Guzmán, Marta
AU - Grueso, Judit
AU - Rodríguez, Olga
AU - Oliveira, Mafalda
AU - Azaro, Analía
AU - Garralda, Elena
AU - Tabernero, Josep
AU - Casanovas, Oriol
AU - Scaltriti, Maurizio
AU - Prat, Aleix
AU - Dienstmann, Rodrigo
AU - Nuciforo, Paolo
AU - Saura, Cristina
AU - Graupera, Mariona
AU - Vivancos, Ana
AU - Rodon, Jordi
AU - Serra, Violeta
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - Purpose: FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multityrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively. Experimental Design: Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient–derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence. Results: High FGFR1–4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1–4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1–4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs. Conclusions: Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1–4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.
AB - Purpose: FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multityrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively. Experimental Design: Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient–derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence. Results: High FGFR1–4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1–4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1–4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs. Conclusions: Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1–4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.
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U2 - 10.1158/1078-0432.CCR-21-1810
DO - 10.1158/1078-0432.CCR-21-1810
M3 - Article
C2 - 34593528
AN - SCOPUS:85121636545
SN - 1078-0432
VL - 28
SP - 137
EP - 149
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -