Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients

Vidal, Joana; Muinelo, Laura; Dalmases, Alba; Jones, Frederick S.; Edelstein, Daniel L.; Iglesias, Mar; Orrillo, Mayra; Abalo, Alicia; Rodríguez, Carmela; Brozos, Elena; Vidal, Yoanis Socarras; Candamio, Sonia; Vázquez, Francisca; Ruiz, Jimmy; Guix, Marta; Visa, Laura; Sikri, V.; Albanell, Joan; Bellosillo, Beatríz; López, Rafael; Montagut, Clara

doi:10.1093/annonc/mdx125

Cited by 299 publications

(336 citation statements)

References 16 publications

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“…First, prior treatment type at time of blood draw or tissue biopsy was not considered. It was previously reported that KRAS status in ctDNA could be affected by specific therapeutic pressure such as administration of EGFR antibodies . Indeed, 7 out of 20 patients who had KRAS alterations only in ctDNA received anti‐EGFR therapies prior to their ctDNA analyses in this series.…”

Section: Discussionmentioning

confidence: 76%

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

Mardinian

Okamura

Kato

et al. 2019

Intl Journal of Cancer

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We investigated the impact of time interval, primary vs. metastatic biopsy site, variant allele fraction (VAF) and histology on concordance of KRAS alterations in tissue vs. circulating tumor DNA (ctDNA), and association of concordance with survival. Blood and tissue were evaluated by next‐generation sequencing in 433 patients with diverse cancers. Altogether, 101 patients (23.3%) had KRAS alterations: 56, ctDNA (12.9%); 81, tissue (18.7%); and 36, both (8.3%). The overall blood and tissue concordance rate for KRAS alterations was 85%, but was mainly driven by the large negative/negative subset. Therefore, specificity of one test for the other was high (88.1–94.3%), while sensitivity was not high (44.4–64.3%) and was lower still in patients with >6 vs. ≤2 months between blood and tissue sampling (31.0–40.9% vs. 51.2–84.0%; p = 0.14 time interval‐dependent sensitivity of blood for tissue; p = 0.003, tissue for blood). Positive concordance rate for KRAS alterations was 57.1% vs. 27.4% (colorectal vs. noncolorectal cancer; p = 0.01), but site of biopsy (primary vs. metastatic) and VAF (%ctDNA) was not impactful. The presence of KRAS alterations in both tests was independently associated with shorter survival from diagnosis (hazard ratio, 1.72; 95% confidence interval, 1.04–2.86) and from recurrent/metastatic disease (1.70; 1.03–2.81). Positive concordance of KRAS alterations between ctDNA and tissue was negatively affected by a longer time period between blood and tissue sampling and was higher in colorectal cancer than in other malignancies. The presence of KRAS alterations in both tests was an independent prognostic factor for poor survival.

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Section: Discussionmentioning

confidence: 76%

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

Mardinian

Okamura

Kato

et al. 2019

Intl Journal of Cancer

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“…The first blinded prospective study that evaluated KRAS mutation status in ctDNA using Intplex, a quantitative PCR‐based method using originally designed specific primers for multiple gene mutations , in mCRC showed high concordance (94%) and specificity (98%) compared with tissue analyses . The OncoBEAM RAS CRC assay is now available as the only test for detecting RAS mutations in ctDNA with European Conformity in vitro diagnostic (CE‐IVD) study; it can accurately detect up to 34 mutations in exons 2, 3, and 4 of KRAS and NRAS genes, using the BEAMing technology . One of the largest cohort prospective studies revealed that the accuracy raised up to 95.6% in patients with liver metastases .…”

Section: Identification Of Biomarkers Related To Resistance To Epidermentioning

confidence: 99%

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Nakamura

Yoshino

2018

The Oncologist

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Multiple genomic changes caused by clonal evolution induced by therapeutic pressure and corresponding intratumoral heterogeneity have posed great challenges for personalized therapy against metastatic colorectal cancer (mCRC) in the past decade. Liquid biopsy has emerged as an excellent molecular diagnostic tool for assessing predominant spatial and temporal intratumoral heterogeneity with minimal invasiveness.Previous studies have revealed that genomic alterations in ,, , and, as well as other cancer-related genes associated with resistance to anti-epidermal growth factor receptor (EGFR) therapy, can be analyzed with high diagnostic accuracy by circulating tumor DNA (ctDNA) analysis. Furthermore, by longitudinally monitoring ctDNAs during anti-EGFR therapy, the emergence of genomic alterations can be detected as acquired resistance mechanisms in specific genes, mainly those associated with the mitogen-activated protein kinase signaling pathway. Analysis of ctDNA can also identify predictive biomarkers to immune checkpoint inhibitors, such as mutations in mismatch repair genes, microsatellite instability-high phenotype, and tumor mutation burden. Some prospective clinical trials evaluating targeted agents for genomic alterations in ctDNA or exploring resistance biomarkers by monitoring of ctDNA are ongoing.To determine the value of ctDNA analysis for decision-making by more accurate molecular marker-based selection of patients and identification of resistance mechanisms to targeted therapies or sensitive biomarkers for immune checkpoint inhibitors, clinical trials must be refined to evaluate the efficacy of study treatment in patients with targetable genomic alterations confirmed by ctDNA analysis, and resistance biomarkers should be explored by monitoring ctDNA in large-scale clinical trials. In the near future, ctDNA analysis will play an important role in precision medicine for mCRC. IMPLICATIONS FOR PRACTICE: Treatment strategies for metastatic colorectal cancer (mCRC) are determined according to the molecular profile, which is confirmed by analyzing tumor tissue. Analysis of circulating tumor DNA (ctDNA) may overcome the limitations of tissue-based analysis by capturing spatial and temporal intratumoral heterogeneity of mCRC. Clinical trials must be refined to test the value of ctDNA analysis in patient selection and identification of biomarkers. This review describes ctDNA analysis, which will have an important role in precision medicine for mCRC.

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“…We previously reported the detection of KRAS mutations in cfDNA from 5 of 55 mCRC patients (9%) with wild-type KRAS in their primary tumors [23]. Other researchers reported that KRAS mutation in cfDNA is a negative biomarker of EGFR blockade chemotherapy [23][24][25][26][27].…”

Section: Predictive Information For Metastatic Diseasementioning

confidence: 98%

“…Some researchers have detected emerging KRAS mutation in cfDNA from patients with secondary resistance to EGFR blockade chemotherapy [24][25][26][28][29][30]. Emerging BRAF mutation [25] and emerging EGFR mutation [26,30] are induced by EGFR blockade.…”

Section: Predictive Information For Metastatic Diseasementioning

confidence: 99%

Liquid Biopsy for the Management of Patients with Colorectal Cancer

et al. 2018

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Background: Liquid biopsy is a collective term that refers to the analysis of tumor-derived biomarkers isolated from biological fluids of cancer patients. Recently, many authors reported the usefulness of liquid biopsy for the management of malignancy. Summary and Key Messages: The peripheral blood of cancer patients is a pool of cells and/or cell products derived from the primary or metastatic tumor, including circulating tumor cells (CTCs), circulating free (cf) DNA or RNA, and exosomes containing proteins, nucleic acids, and lipids. CTCs are tumor cells that can be isolated from peripheral blood. Free circulating DNA with a tumor-specific mutation is called circulating tumor DNA (ctDNA). Some patients who undergo curative surgery experience recurrent disease, which can be due to the presence of minimal residual disease (MRD). Thus, MRD indicates a high risk of relapse. Detection of ctDNA or CTC after surgery is a direct proof of MRD. Molecular volume (e.g., the number of CTCs and level of ctDNA) might reflect tumor burden, thus high molecular volume may indicate poor prognosis. The most notable application of liquid biopsy in cancer is to understand spatial and temporal heterogeneities. Heterogeneity is one of the causes of refractoriness and hampers prediction of chemotherapeutic effect. Emerging mutations that are not present in primary tumors but are found in their metastases can be detected in ctDNA. Some colorectal cancer patients with wild-type RAS do not respond to epidermal growth factor receptor blockade. In a subset of these patients, RAS mutation is detected in ctDNA, indicating heterogeneity.

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Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients

Cited by 299 publications

References 16 publications

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

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

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Liquid Biopsy for the Management of Patients with Colorectal Cancer

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