Concordance between TP53 alterations in blood and tissue: impact of time interval, biopsy site, cancer type and circulating tumor DNA burden.

We examined the impact of spatial, temporal, histologic, and quantitative factors on concordance between TP53 alterations in tissue DNA vs in circulating tumor DNA (ctDNA). Four hundred and thirty-three patients underwent next-generation sequencing (NGS) in which both tissue and blood samples were evaluated. TP53 was detected in 258 of 433 patients (59.6%); 215 had tissue TP53 alterations (49.7%); 159, ctDNA (36.7%); and 116, both tissue and ctDNA (27.8%). Overall concordance rate between ctDNA and tissue biopsies for TP53 alterations was 67.2%; positive concordance was 45.0%. Overall concordance for TP53 did not vary among patients with ≤ 2 months vs > 6 months between test samples; however, positive concordance trended higher when time intervals between test samples were shorter, suggesting that the lack of difference in overall concordance may be due to the large number of negative/negative tests. There was a trend toward higher overall concordance based on biopsy site (metastatic vs primary) (P = 0.07) and significantly higher positive concordance if the tissue biopsy site was a metastatic lesion (P = 0.03). Positive concordance significantly decreased in noncolorectal cancer patients vs colorectal cancer patients (P = 0.02). Finally, higher %ctDNA was associated with higher concordance rates between blood and tissue (P < 0.001). Taken together, these data indicate that both blood and tissue DNA sequencing are necessary to evaluate the full scope of TP53 alterations, and that concordance rates may be related to multiple factors including, but not limited to, amount of ctDNA, histologic context, and site of tissue biopsy.

Next-Generation Sequencing in the Clinical Setting Clarifies Patient Characteristics and Potential Actionability.

Enhancements in clinical-grade next-generation sequencing (NGS) have fueled the advancement of precision medicine in the clinical oncology field. Here, we survey the molecular profiles of 1,113 patients with diverse malignancies who successfully underwent clinical-grade NGS (236-404 genes) in an academic tertiary cancer center. Among the individual tumors examined, the majority showed at least one detectable alteration (97.2%). Among 2,045 molecular aberrations was the involvement of 302 distinct genes. The most commonly altered genes were TP53 (47.0%), CDKN2A (18.0%), TERT (17.0%), and KRAS (16.0%), and the majority of patients had tumors that harbored multiple alterations. Tumors displayed a median of four alterations (range, 0-29). Most individuals had at least one potentially actionable alteration (94.7%), with the median number of potentially actionable alterations per patient being 2 (range, 0-13). A total of 1,048 (94.2%) patients exhibited a unique molecular profile, with either genes altered or loci within the gene(s) altered being distinct. Approximately 13% of patients displayed a genomic profile identical to at least one other patient; although genes altered were the same, the affected loci may have differed. Overall, our results underscore the complex heterogeneity of malignancies and argue that customized combination therapies will be essential to optimize cancer treatment regimens. Cancer Res; 77(22); 6313-20. ©2017 AACR.