Artigo Revisado por pares

Correlation of measurements of tumor heterogeneity based on next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) with clinical outcomes in STEAM, a prospective, randomized, multicenter study in metastatic colorectal cancer (mCRC).

2018; Lippincott Williams & Wilkins; Volume: 36; Issue: 15_suppl Linguagem: Inglês

10.1200/jco.2018.36.15_suppl.3545

ISSN

1527-7755

Autores

Stephanie J. Yaung, Nalin Tikoo, Alan Nicholas, Nicolas Sommer, Johanna C. Bendell, Herbert I. Hurwitz, Richard Price, John F. Palma, John J. Lee, Fergal Casey,

Tópico(s)

Genetic factors in colorectal cancer

Resumo

3545 Background: STEAM (clinical trial NCT01765582) assessed efficacy and safety of concurrent and sequential FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for first-line treatment of mCRC. The AVENIO ctDNA Expanded and Surveillance Kits (Research Use Only) were used to detect somatic mutations by NGS in tissue, and pre- and post-induction plasma samples. Methods: Plasma-based molecular measures of tumor heterogeneity were defined as: 1) Plasma Recovery Rate (PRR), a ratio of shared plasma and matched tissue variants to total plasma variants; 2) Mutant-Allele Tumor Heterogeneity (MATH), a measure of variant allelic frequency dispersion, applied here to plasma; and 3) Multi-Variant Gene Count (MVGC), a count of genes harboring > 1 somatic mutations in plasma. Results: Overall, greater pre-induction tissue-plasma discordance correlated with shorter OS, and subjects with complete tissue-plasma concordance (defined as PRR = 1, suggesting monoclonality) had longer PFS (18.3 vs 9.5 mo, HR 0.43, 95% CI 0.2 - 0.91, logrank p = 0.023). High plasma allele frequency dispersion, assessed as MATH in the top quartile, correlated with shorter PFS in pre-induction plasma (8.1 vs 11.7 mo, HR 1.8, 95% CI 1.1 - 3.1, logrank p = 0.026) and in post-induction plasma (7.4 vs 12.2 mo, HR 2.9, 95% CI 1.7 - 5.2, logrank p = 0.00012). Similar trends were seen for OS. Subjects with > 1 somatic mutation in a gene, classified as MVGC > 0, in post-induction plasma had shorter OS. An increase in MVGC from pre- to post-induction correlated with shorter OS (14.8 vs 26.4 mo, HR 4.6, 95% CI 1.9 - 10.9, logrank p = 0.00029). Conclusions: Analyses with AVENIO ctDNA Kits on STEAM reveal the potential prognostic value of measuring plasma-based tumor heterogeneity, with higher heterogeneity correlating strongly with poor outcomes. Pre-induction, a lower rate of recovery of plasma variants in tissue and high plasma dispersion correlated with shorter survival. Post-induction, high plasma dispersion and intragenic heterogeneity correlated with shorter survival. These hypothesis-generating results require further validation.

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