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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

1899 - ctDNA assays identify alterations in RAS, EGFR, and cMET that are unique to RAS-WT patients progressing on anti-EGFR therapy

Date

21 Oct 2018

Session

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

Topics

Targeted Therapy;  Translational Research

Tumour Site

Gastrointestinal Cancers

Presenters

Rohan Gupta

Citation

Annals of Oncology (2018) 29 (suppl_8): viii150-viii204. 10.1093/annonc/mdy281

Authors

R. Gupta, D. Chevalier, J. Saluja, C. Lau, C. Wang, M. Fakih

Author affiliations

  • Department Of Medical Oncology And Therapeutics, City of Hope, 91010 - Duarte/US

Resources

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Abstract 1899

Background

Circulating tumor DNA (ctDNA) assays and tumor sequencing provide insight to tumor heterogeneity and mechanism of resistance in patients with MCRC. Direct comparisons between Guardant360® (G360) ctDNA panel and the comprehensive Foundation One® NGS (FO) panel in MCRC patients (pts) are limited.

Methods

We identified MCRC pts with FO at diagnosis and subsequent G360 ctDNA assays. Pts were divided into 3 categories based on ctDNA collection date: 1) ctDNA testing prior to any treatment, 2) ctDNA following non-anti-EGFR therapy and 3) ctDNA following anti-EGFR progression (PD). We compared genomic alterations by FO and G360 within the same pts to characterize clonal evolution and its impact on outcome.

Results

43 pts with MCRC with FO had at least one ctDNA assay. High concordance between ctDNA and FO was noted in untreated pts (n = 11) for common oncogenic drivers, including RAS and BRAF. In 2/11 cases, 2 RAS mutations were identified on G360 only: NRAS E31D (unknown significance), and a low frequency G12D (0.3%) which may have been below the reporting limits for FO. Concordance was also noted in pts pre-treated with non-anti-EGFR therapy (n = 11). In contrast, ctDNA assays of RAS-wild type pts with PD following anti-EGFR (n = 19) showed a high rate of emergent activating KRAS [Q61H (3/19 cfDNA 0.08% -9.8%) and L19F (1/19 cfDNA 1.1%)], EGFR V441G (3/19 cfDNA 0.4%-7.9%), and FGFR2 mutations (2/19 cfDNA 1.8%-2.1%), suggesting that these are common mechanisms of resistance[VR1] . 1 pt had emergence of EGFR V441G mutation without any KRAS or NRAS mutations. Only 3 pts had serial ctDNA assays. 1 pt with BRAF V600E mutation developed cMET amplification after progressing following 6 months of response on BRAF + MEK + EGFR inhibitors. Upon withdrawal of targeted therapy, his cMET amplification resolved and he responded again to BRAF + EGFR inhibitors (5 months and ongoing), confirming clonal evolution in response to BRAF inhibitors and their withdrawal.

Conclusions

In untreated and progressing anti-EGFR naïve pts, ctDNA provides an accurate assessment of oncogenic RAS and BRAF status. Clonal evolution is captured on ctDNA in response to anti-EGFR therapy and extends beyond emerging RAS mutations to EGFR mutations and cMET amplification.

Clinical trial identification

Legal entity responsible for the study

Marwan Fakih.

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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