Poster Presentation 29th Lorne Cancer Conference 2017

Circulating tumor DNA analysis and functional imaging provide complementary approaches for comprehensive disease monitoring in metastatic melanoma (#289)

Stephen Q Wong 1 , Jeanette M Raleigh 1 , Jason Callahan 1 , Ismael A Vergara 1 , Sarah Ftouni 1 , Athena Hatzimihalis 1 , Andrew J Colebatch 1 , Jason Li 1 , Tim Semple 1 , Ken Doig 1 , Chris Mintoff 1 , Devbarna Sinha 1 , Paul Yeh 1 , Maria Joao Silva 1 , Kathryn Alsop 1 , Heather Thorne 1 , David D Bowtell 1 , David Gyorki 1 , Gisela Mir 1 , Carleen Cullinane 1 , Damien Kee 1 , Benjamin Brady 1 , Fergal Kelleher 1 , Mark A Dawson 1 , Tony Papenfuss 1 , Mark Shackleton 1 , Rod Hicks 1 , Grant A McArthur 1 , Shahneen Sandhu 1 , Sarah-Jane Dawson 1
  1. Peter MacCallum Cancer Centre, Melbourne, VICTORIA, Australia

Background. Circulating tumor DNA (ctDNA) allows non-invasive molecular disease monitoring across a range of malignancies. In metastatic melanoma, the extent to which ctDNA reflects changes in metabolic disease burden assessed by [18F]-fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) is unknown. We sought to assess the role of ctDNA analysis in combination with FDG-PET, to monitor tumor burden and genomic heterogeneity throughout treatment.

Methods. We performed a comprehensive analysis of serial ctDNA and FDG-PET in fifty-two patients receiving systemic therapy for metastatic melanoma. Next generation sequencing and digital PCR were used to analyse ctDNA across 312 serial plasma samples. 

Results. ctDNA levels were monitored in patients with BRAF mutant, NRAS mutant and “wildtype” disease. BRAF and NRAS ctDNA levels correlated closely with changes in metabolic disease burden throughout treatment with both targeted and immunotherapies. TERT-promoter mutant ctDNA levels also paralleled changes in tumor burden providing an alternative marker for disease monitoring. Notably, subcutaneous and cerebral disease sites were not well represented in plasma, even in cases with substantial disease burden observed by FDG-PET. Early changes in ctDNA and metabolic disease burden were important indicators of treatment response. Patients with an early decrease in ctDNA post treatment had improved progression free survival compared to patients in whom ctDNA levels remained unchanged or increased over time (HR 2.6, p=0.05). In patients with disease progression, ctDNA analysis contributed key molecular information through the identification of putative resistance mechanisms to targeted therapy. A detailed comparison of the genomic architecture of plasma and multi-regional tumor biopsies at autopsy in three cases revealed the ability of ctDNA to comprehensively capture genomic heterogeneity across multiple disease sites. 

Conclusions. Together, our findings highlight the powerful role of ctDNA in metastatic melanoma as a complementary modality to functional imaging allowing real-time monitoring of both tumor burden and genomic changes throughout therapy.