Editors' ChoiceCancer

Confronting the challenges of precision oncology

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Science Translational Medicine  01 Jun 2016:
Vol. 8, Issue 341, pp. 341ec86
DOI: 10.1126/scitranslmed.aag1702

With an increased understanding of cancer genomics and tumor biology, a number of therapeutics have been designed to target cancer-specific genomic alterations. However, targeted therapies are not always effective in cancer patients even if the target alteration is detected. There are a number of potential explanations for this, including the possibility that the targeted mutation is not a key driver for that patient’s tumor. In a recent study, Pearson et al. report results of an early phase clinical trial investigating the selective fibroblast growth factor receptor (FGFR) inhibitor, AZD4547, for patients whose tumors harbor FGFR1 or FGFR2 genomic amplification. Over 300 metastatic cancer patients were screened for the study, and 8 FGFR1-amplified breast and 9 FGFR2-amplified gastroesophageal (GE) cancer patients were treated. Of those, 1 breast and 3 GE cancer patients responded to AZD4547, with a median progression-free survival of 6.6 months.

The investigators explored differences between responders and nonresponders and found that tumors with higher copy number and higher clonality of FGFR gain (>99% of tumor cells amplified) were more likely to respond to AZD4547. High copy number of FGFR2 was also associated with higher mRNA and protein expression of both wild type FGFR2 and its oncogenic isoform. The authors used pretreatment biopsies from two responder patients to generate patient-derived xenografts and found that these xenografts’ responses to AZD4547 were similar to those observed in the clinic. Extending these observations to cell line models, higher-level FGFR amplification was associated with increased FGFR autophosphorylation, enhanced sensitivity to AZD4547, and a distinct reliance on phosphoinositide 3-kinase signaling compared with other FGFR-amplified cell lines.

Based on these findings, it is possible that patient selection for high-level clonal amplifications could identify patients most likely to respond to AZD4547. Screening large numbers of patients for infrequent alterations using tissue-based genomic approaches has its challenges and often does not capture tumor evolution and heterogeneous populations. Therefore, the study investigators assessed and confirmed that high level FGFR amplification was detectable noninvasively in responder patients using circulating tumor DNA, possibly paving the way for future biomarker-enriched trials.

Overall, this study highlights the challenges and potential of prospective translational clinical trials to better define and characterize mechanisms of response to targeted therapeutics. Though small, this study shows that it is feasible to incorporate patient-derived preclinical models and liquid biopsies for deeper exploration across heterogeneous patient populations.

A. Pearson et al., High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial. Cancer Discov. 10.1158/2159-8290.CD-15-1246 (2016). [Abstract]

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