Reference Detail

Ref Type

Journal Article

PMID

(27179038)

Authors

Pearson A, Smyth E, Babina IS, Herrera-Abreu MT, Tarazona N, Peckitt C, Kilgour E, Smith NR, Geh C, Rooney C, Cutts R, Campbell J, Ning J, Fenwick K, Swain A, Brown G, Chua S, Thomas A, Johnston SR, Ajaz M, Sumpter K, Gillbanks A, Watkins D, Chau I, Popat S, Cunningham D, Turner NC

Title

High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	6	8	2016 Aug	838-851	Cancer Discov

URL

Abstract Text

FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy.Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients. Cancer Discov; 6(8); 838-51. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 amp	breast cancer	no benefit	Fexagratinib	Phase II	Actionable	In a Phase II clinical trial, treatment with AZD4547 resulted in a response rate of 12.5% (1/8) in patients with FGFR1-amplified breast cancer, and did not meet the predetermined criteria for efficacy (PMID: 27179038).	27179038
FGFR2 amp	stomach cancer	sensitive	PD173074	Preclinical - Cell culture	Actionable	In a preclinical study, FGFR2-amplified gastric cancer cell lines demonstrated sensitivity to PD173074 in culture, with cell lines with high-level FGFR2 amplification displaying higher sensitivity compared to cell lines with low-level amplification (PMID: 27179038).	27179038
FGFR2 amp	stomach cancer	sensitive	Fexagratinib	Phase II	Actionable	In a Phase II clinical trial, treatment with AZD4547 resulted in a 33% (3/9) response rate in patients with FGFR2-amplified gastroesophageal cancer, and high-level amplification was associated with clinical response (PMID: 27179038).	27179038