Temporal and spatial effects and survival outcomes associated with concordance between tissue and blood <i>KRAS</i> alterations in the pan‐cancer setting

Mardinian, Kristina; Okamura, Ryosuke; Kato, Shumei; Kurzrock, Razelle

doi:10.1002/ijc.32510

Cited by 20 publications

(21 citation statements)

References 33 publications

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“…It should be noted that the sensitivity of ctDNA for tissue DNA in detecting alterations was lower, compared with that of tissue DNA for ctDNA (57% [29 of 51] versus 88% [29 of 33] for TP53, and 47% [28 of 60] versus 100% [28 of 28] for KRAS, respectively). Other studies have found similar results [45][46][47]. Discordant cases that were positive in tissue and negative in ctDNA have been previously explained by low tumor load in surgically resectable cases [43,44].…”

Section: Discussionsupporting

confidence: 69%

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

et al. 2019

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Background: Treatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy. Methods: ctDNA was analyzed in 112 patients with PDAC (54-73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed. Results:The most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0-6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85-10.24 [multivariate, P = 0.001]). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months.Conclusions: Our findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival.

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Section: Discussionsupporting

confidence: 69%

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

et al. 2019

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“…By contrast, higher rates of "all same TP53 mutations" categories were observed for colorectal cancer, perhaps reflecting higher frequency of ctDNA detection in this tumor type (14). Interestingly, we previously found colorectal cancers (versus other malignancies) to also have higher concordance between blood and tissue results for KRAS alterations (36).…”

Section: Discussionmentioning

confidence: 73%

Survival Implications of the Relationship between Tissue versus Circulating Tumor DNA TP53 Mutations—A Perspective from a Real-World Precision Medicine Cohort

Rosenberg

Okamura

Kato

et al. 2020

Molecular Cancer Therapeutics

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Interrogating the genomics of circulating tumor DNA (ctDNA) (the liquid biopsy) has advantages in patients in whom tissue biopsy is difficult. However, the reported concordance between genomic analysis of tissue DNA and ctDNA is variable among studies. Herein, we characterized the clinical implications of the relationship between mutations in TP53 genes in tissue DNA versus ctDNA. The molecular profiles of both liquid (Guardant Health) and tissue biopsies (Foundation Medicine) from 433 patients were analyzed (pan-cancer setting). In 71/433 (16%) cases, all same TP53 mutations were detected in both tissue DNA and ctDNA; 18/433 (4%), same mutation plus additional mutation/mutations; 27/433 (6%), different TP53 mutations. In 99/433 (23%) cases, TP53 mutations were detected only in tissue DNA; 43/433 (10%), only in ctDNA; and in 175/433 (40%), no TP53 mutations were detected in either test. When TP53 mutations were identical in tissue and ctDNA, the alterations were enriched for nonsense mutations, and survival was significantly shorter in multivariate analysis (as compared to different mutations in ctDNA versus tissue or no mutations); this finding was independent of tumor type, time interval between tests, and the %ctDNA for TP53 mutations. In summary, in 16% of 433 patients with diverse cancers, TP53 mutations were identical in tissue DNA and ctDNA. In these individuals, the alterations were enriched for stop-gain (nonsense) mutations (results in a premature termination codon). Though unknown confounders cannot be ruled out, these patients fared significantly worse than those whose ctDNA and tissue DNA harbored different TP53 mutation portfolios or no TP53 mutations.

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“…Regarding histologic effects, overall TP53 concordance of blood vs tissue did not differ between colorectal and noncolorectal cancer, but positive concordance was higher in colorectal cancer (60.9% vs 41.5%; P = 0.02). Previous studies have also shown high concordance for blood and tissue alterations, such as those in the KRAS, NRAS , APC, and BRAF genes, in colorectal cancer (Grasselli et al , 2017; Gregg et al , 2018; Kato et al , 2019; Mardinian et al , 2019).…”

Section: Discussionmentioning

confidence: 87%

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

2020

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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.

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Temporal and spatial effects and survival outcomes associated with concordance between tissue and blood KRAS alterations in the pan‐cancer setting

Cited by 20 publications

References 33 publications

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

Survival Implications of the Relationship between Tissue versus Circulating Tumor DNA TP53 Mutations—A Perspective from a Real-World Precision Medicine Cohort

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

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