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Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies.

Janku F, Angenendt P, Tsimberidou AM, Fu S, Naing A, Falchook GS, Hong DS, Holley VR, Cabrilo G, Wheler JJ, Piha-Paul SA, Zinner RG, Bedikian AY, Overman MJ, Kee BK, Kim KB, Kopetz ES, Luthra R, Diehl F, Meric-Bernstam F, Kurzrock R - Oncotarget (2015)

Bottom Line: Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS, and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures.Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.75, 95% confidence interval [CI] 0.63 - 0.88), in 99% cases for EGFR mutations (kappa = 0.90, 95% CI 0.71- 1.00), in 83% cases for KRAS mutations (kappa = 0.67, 95% CI 0.54 - 0.80) and in 91% cases for PIK3CA mutations (kappa = 0.65, 95% CI 0.46 - 0.85).Patients (n = 41) with > 1% of KRAS mutant cfDNA had a shorter median survival compared to 20 patients with </= 1% of KRAS mutant DNA (4.8 vs. 7.3 months, p=0.008).

View Article: PubMed Central - PubMed

Affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

ABSTRACT
Cell-free (cf) DNA in the plasma of cancer patients offers an easily obtainable source of biologic material for mutation analysis. Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS, and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures. Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.75, 95% confidence interval [CI] 0.63 - 0.88), in 99% cases for EGFR mutations (kappa = 0.90, 95% CI 0.71- 1.00), in 83% cases for KRAS mutations (kappa = 0.67, 95% CI 0.54 - 0.80) and in 91% cases for PIK3CA mutations (kappa = 0.65, 95% CI 0.46 - 0.85). Patients (n = 41) with > 1% of KRAS mutant cfDNA had a shorter median survival compared to 20 patients with 1% of mutant cfDNA (BRAF, EGFR, KRAS, or PIK3CA) had a shorter median survival compared to 33 patients with

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(A) In 61 patients with KRAS mutations in cfDNA, 31 patients with scores of 0–1 had longer median survival than 30 patients with RMH scores of 2–3 (5.7 months, 95% CI 4.4–7.0 vs. 4.8 months, 95% CI 3.9–5.7; p = 0.036). (B) In a combined analysis of 105 patients with any cfDNA mutation, 57 patients with RMH scores of 0–1 had longer median survival than did 48 patients with RMH scores of 2–3 (7.4 months, 95% CI 4.9–9.9 vs. 5.3 months, 95% CI 4.2–6.4; p = 0.029). (C) In a combined analysis of 105 patients with any cfDNA mutation, 41 patients with MDACC scores of 0–2 had longer median survival than 64 patients with MDACC scores of 3–5 (7.4 months, 95% CI 4.5–10.3 vs. 5.3 months, 95% CI 4.3–6.3; p = 0.002).
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Figure 2: (A) In 61 patients with KRAS mutations in cfDNA, 31 patients with scores of 0–1 had longer median survival than 30 patients with RMH scores of 2–3 (5.7 months, 95% CI 4.4–7.0 vs. 4.8 months, 95% CI 3.9–5.7; p = 0.036). (B) In a combined analysis of 105 patients with any cfDNA mutation, 57 patients with RMH scores of 0–1 had longer median survival than did 48 patients with RMH scores of 2–3 (7.4 months, 95% CI 4.9–9.9 vs. 5.3 months, 95% CI 4.2–6.4; p = 0.029). (C) In a combined analysis of 105 patients with any cfDNA mutation, 41 patients with MDACC scores of 0–2 had longer median survival than 64 patients with MDACC scores of 3–5 (7.4 months, 95% CI 4.5–10.3 vs. 5.3 months, 95% CI 4.3–6.3; p = 0.002).

Mentions: In 61 patients with KRAS mutations in cfDNA, 31 patients with RMH scores of 0–1 had longer median survivals than 30 patients with RMH scores of 2–3 (5.7 months, 95% CI 4.4–7.0 vs. 4.8 months, 95% CI 3.9–5.7; p = 0.036, Figure 2A). In multivariable analysis, which included KRAS mutations in cfDNA (</= 1% vs. > 1%) and the RMH score (0–1 vs. 2–3), patients with KRAS mutations in </= 1% of cfDNA had a trend toward a longer survival compared to patients with KRAS mutations in > 1% of cfDNA (hazard ratio [HR] 0.53, 95% CI 0.27–1.03, p = 0.06).


Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies.

Janku F, Angenendt P, Tsimberidou AM, Fu S, Naing A, Falchook GS, Hong DS, Holley VR, Cabrilo G, Wheler JJ, Piha-Paul SA, Zinner RG, Bedikian AY, Overman MJ, Kee BK, Kim KB, Kopetz ES, Luthra R, Diehl F, Meric-Bernstam F, Kurzrock R - Oncotarget (2015)

(A) In 61 patients with KRAS mutations in cfDNA, 31 patients with scores of 0–1 had longer median survival than 30 patients with RMH scores of 2–3 (5.7 months, 95% CI 4.4–7.0 vs. 4.8 months, 95% CI 3.9–5.7; p = 0.036). (B) In a combined analysis of 105 patients with any cfDNA mutation, 57 patients with RMH scores of 0–1 had longer median survival than did 48 patients with RMH scores of 2–3 (7.4 months, 95% CI 4.9–9.9 vs. 5.3 months, 95% CI 4.2–6.4; p = 0.029). (C) In a combined analysis of 105 patients with any cfDNA mutation, 41 patients with MDACC scores of 0–2 had longer median survival than 64 patients with MDACC scores of 3–5 (7.4 months, 95% CI 4.5–10.3 vs. 5.3 months, 95% CI 4.3–6.3; p = 0.002).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494976&req=5

Figure 2: (A) In 61 patients with KRAS mutations in cfDNA, 31 patients with scores of 0–1 had longer median survival than 30 patients with RMH scores of 2–3 (5.7 months, 95% CI 4.4–7.0 vs. 4.8 months, 95% CI 3.9–5.7; p = 0.036). (B) In a combined analysis of 105 patients with any cfDNA mutation, 57 patients with RMH scores of 0–1 had longer median survival than did 48 patients with RMH scores of 2–3 (7.4 months, 95% CI 4.9–9.9 vs. 5.3 months, 95% CI 4.2–6.4; p = 0.029). (C) In a combined analysis of 105 patients with any cfDNA mutation, 41 patients with MDACC scores of 0–2 had longer median survival than 64 patients with MDACC scores of 3–5 (7.4 months, 95% CI 4.5–10.3 vs. 5.3 months, 95% CI 4.3–6.3; p = 0.002).
Mentions: In 61 patients with KRAS mutations in cfDNA, 31 patients with RMH scores of 0–1 had longer median survivals than 30 patients with RMH scores of 2–3 (5.7 months, 95% CI 4.4–7.0 vs. 4.8 months, 95% CI 3.9–5.7; p = 0.036, Figure 2A). In multivariable analysis, which included KRAS mutations in cfDNA (</= 1% vs. > 1%) and the RMH score (0–1 vs. 2–3), patients with KRAS mutations in </= 1% of cfDNA had a trend toward a longer survival compared to patients with KRAS mutations in > 1% of cfDNA (hazard ratio [HR] 0.53, 95% CI 0.27–1.03, p = 0.06).

Bottom Line: Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS, and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures.Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.75, 95% confidence interval [CI] 0.63 - 0.88), in 99% cases for EGFR mutations (kappa = 0.90, 95% CI 0.71- 1.00), in 83% cases for KRAS mutations (kappa = 0.67, 95% CI 0.54 - 0.80) and in 91% cases for PIK3CA mutations (kappa = 0.65, 95% CI 0.46 - 0.85).Patients (n = 41) with > 1% of KRAS mutant cfDNA had a shorter median survival compared to 20 patients with </= 1% of KRAS mutant DNA (4.8 vs. 7.3 months, p=0.008).

View Article: PubMed Central - PubMed

Affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

ABSTRACT
Cell-free (cf) DNA in the plasma of cancer patients offers an easily obtainable source of biologic material for mutation analysis. Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS, and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures. Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.75, 95% confidence interval [CI] 0.63 - 0.88), in 99% cases for EGFR mutations (kappa = 0.90, 95% CI 0.71- 1.00), in 83% cases for KRAS mutations (kappa = 0.67, 95% CI 0.54 - 0.80) and in 91% cases for PIK3CA mutations (kappa = 0.65, 95% CI 0.46 - 0.85). Patients (n = 41) with > 1% of KRAS mutant cfDNA had a shorter median survival compared to 20 patients with 1% of mutant cfDNA (BRAF, EGFR, KRAS, or PIK3CA) had a shorter median survival compared to 33 patients with

No MeSH data available.


Related in: MedlinePlus