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FGFR1 Antibody Validation and Characterization of FGFR1 Protein Expression in ER+ Breast Cancer.

ABSTRACT: Clinical trials in patients with ER+ breast cancer with or without FGFR pathway somatic alterations have shown limited clinical benefit from treatment with FGFR tyrosine kinase inhibitors alone or in combination with endocrine therapy. This is likely because of an inadequate predictive biomarker to select appropriate patients. In this study, we evaluated 4 anti-FGFR1 antibodies in breast cancer cell lines and patient-derived xenografts with FGFR1 amplification. We correlated D8E4 expression in 209 tumors from postmenopausal patients with stage I-III operable ER+ breast cancer with FGFR1 amplification status as determined by fluorescence in situ hybridization. FGFR1 amplification was identified in 10% of tumors (21/209), 80% of which exhibited membranous FGFR1 expression; however, only 50% of amplified cases showed strong, complete membranous staining (3+) based on established criteria to score HER2 by immunohistochemistry. These findings suggest the combined evaluation of FGFR1 status by immunohistochemistry and fluorescence in situ hybridization may need to be incorporated into the selection of patients for trials with FGFR inhibitors.

SUBMITTER: Gonzalez-Ericsson PI

PROVIDER: S-EPMC9547979 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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FGFR1 Antibody Validation and Characterization of FGFR1 Protein Expression in ER+ Breast Cancer.

Gonzalez-Ericsson Paula I PI Servetto Alberto A Formisano Luigi L Sánchez Violeta V Mayer Ingrid A IA Arteaga Carlos L CL Sanders Melinda E ME

Applied immunohistochemistry & molecular morphology : AIMM 20220912 9

Clinical trials in patients with ER+ breast cancer with or without FGFR pathway somatic alterations have shown limited clinical benefit from treatment with FGFR tyrosine kinase inhibitors alone or in combination with endocrine therapy. This is likely because of an inadequate predictive biomarker to select appropriate patients. In this study, we evaluated 4 anti-FGFR1 antibodies in breast cancer cell lines and patient-derived xenografts with FGFR1 amplification. We correlated D8E4 expression in 2 ...[more]

PMID: 36083147

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Project description:BackgroundFGFR1 amplification, but not overexpression, has been related to adverse prognosis in hormone-positive breast cancer (HRPBC). Whether FGFR1 overexpression and amplification are correlated, what is their distribution among luminal A or B HRPBC, and if there is a potential different prognostic role for amplification and overexpression are currently unknown features. The role of FGFR1 inhibitors in HRPBC is also unclear.MethodsFGFR1 amplification (FISH) and overexpression (RNAscope) were investigated in a N = 251 HRPBC patients cohort and the METABRIC cohort; effects on survival and FISH-RNAscope concordance were determined. We generated hormonal deprivation resistant (LTED-R) and FGFR1-overexpressing cell line variants of the ER+ MCF7 and T47-D and the ER+, FGFR1-amplified HCC1428 cell lines. The role of ER, CDK4/6, and/or FGFR1 blockade alone or in combinations in Rb phosphorylation, cell cycle, and survival were studied.ResultsFGFR1 overexpression and amplification was non-concordant in > 20% of the patients, but both were associated to a similar relapse risk (~ 2.5-fold; P < 0.05). FGFR1 amplification or overexpression occurred regardless of the luminal subtype, but the incidence was higher in luminal B (16.3%) than A (6.6%) tumors; P < 0.05. The Kappa index for overexpression and amplification was 0.69 (P < 0.001). Twenty-four per cent of the patients showed either amplification and/or overexpression of FGFR1, what was associated to a hazard ratio for relapse of 2.6 (95% CI 1.44-4.62, P < 0.001). In vitro, hormonal deprivation led to FGFR1 overexpression. Primary FGFR1 amplification, engineered mRNA overexpression, or LTED-R-acquired FGFR1 overexpression led to resistance against hormonotherapy alone or in combination with the CDK4/6 inhibitor palbociclib. Blocking FGFR1 with the kinase-inhibitor rogaratinib led to suppression of Rb phosphorylation, abrogation of the cell cycle, and resistance-reversion in all FGFR1 models.ConclusionsFGFR1 amplification and overexpression are associated to similar adverse prognosis in hormone-positive breast cancer. Capturing all the patients with adverse prognosis-linked FGFR1 aberrations requires assessing both features. Hormonal deprivation leads to FGFR1 overexpression, and FGFR1 overexpression and/or amplification are associated with resistance to hormonal monotherapy or in combination with palbociclib. Both resistances are reverted with triple ER, CDK4/6, and FGFR1 blockade.

Dataset Information

FGFR1 Antibody Validation and Characterization of FGFR1 Protein Expression in ER+ Breast Cancer.

Publications

FGFR1 Antibody Validation and Characterization of FGFR1 Protein Expression in ER+ Breast Cancer.

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