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PURPOSE: Circulating tumor DNA (ctDNA) genotyping on the basis of next-generation sequencing (NGS) may guide targeted therapy for metastatic colorectal cancer (mCRC). However, the validity of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment and the efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA results remains unclear. PATIENTS AND METHODS: The performance of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment was compared with that of a validated polymerase chain reaction–based tissue testing in patients with mCRC enrolled in the GOZILA study, a nationwide plasma genotyping study. The primary end points were concordance rate, sensitivity, and specificity. The efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA were also evaluated. RESULTS: In 212 eligible patients, the concordance rate, sensitivity, and specificity were 92.9% (95% CI, 88.6 to 96.0), 88.7% (95% CI, 81.1 to 94.0), and 97.2% (95% CI, 92.0 to 99.4) for RAS and 96.2% (95% CI, 92.7 to 98.4), 88.0% (95% CI, 68.8 to 97.5), and 97.3% (95% CI, 93.9 to 99.1) for BRAF V600E, respectively. In patients with a ctDNA fraction of ≥1.0%, sensitivity rose to 97.5% (95% CI, 91.2 to 99.7) and 100% (95% CI, 80.5 to 100.0) for RAS and BRAF V600E mutations, respectively. In addition to a low ctDNA fraction, previous chemotherapy, lung and peritoneal metastases, and interval between dates of tissue and blood collection were associated with discordance. The progression-free survival of anti-EGFR therapy and BRAF-targeted treatment was 12.9 months (95% CI, 8.1 to 18.5) and 3.7 (95% CI, 1.3 to not evaluated) months, respectively, for matched patients with RAS/BRAF V600E results by ctDNA. CONCLUSION: ctDNA genotyping effectively detected RAS/BRAF mutations, especially with sufficient ctDNA shedding. Clinical outcomes support ctDNA genotyping for determining the use of anti-EGFR and BRAF-targeted therapies in patients with mCRC. Using a large-scale plasma genomic profiling program (SCRUM-Japan GOZILA), we validated ctDNA genotyping for RAS and BRAF V600E in metastatic colorectal cancer comparing with a validated tissue PCR-based testing. [ABSTRACT FROM AUTHOR]

PURPOSE: Low concordance between plasma-based and tissue-based tests for determining the RAS mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology. MATERIALS AND METHODS: We investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315). RESULTS: Of 1,187 patients with mCRC enrolled in GOZILA, 138 were eligible (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only metastases). The concordance of RAS / BRAF status between Guaradant360 and tissue in vitro diagnostic tests was 95.9% in patients with liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only metastases. ctDNA fraction, as measured by the median maximum variant allelic fraction (max VAF), and median number of detected variants were 23.1% and five in liver-only, 6.0% and five in lymph node-only, 0.4% and three in peritoneum-only, and 0.4% and three in lung-only metastases, respectively (all P <.001, Kruskal-Wallis test). Few patients with liver-only (2.0%) and lymph node-only metastasis (13.3%) had a max VAF < 0.2%, which is required to ensure a detection limit of 95%, but max VAF was more frequently < 0.2% in patients with lung-only (27.7%) or peritoneum-only metastasis (29.6%). CONCLUSION: Patients with lung-only and peritoneum-only metastatic disease have significantly lower levels of ctDNA, suggesting decreased clinical sensitivity for subclonal variants. This observation suggests that such patients may benefit from concurrent tissue and plasma testing to provide optimal genotyping for subsequent therapy selection. [ABSTRACT FROM AUTHOR]

PURPOSE: Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard. PATIENTS AND METHODS: The performance of plasma-based MSI assessment using Guardant360, a next-generation sequencing–based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction–based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study. The primary end points were overall percent agreement, positive percent agreement (PPA), and negative percent agreement. The efficacy of immune checkpoint inhibitor therapy was also evaluated. RESULTS: In 658 patients with advanced GI cancers who underwent both plasma and tissue testing for MSI, the overall percent agreement, PPA, and negative percent agreement were 98.2% (95% CI, 96.8 to 99.1), 71.4% (95% CI, 47.8 to 88.7), and 99.1% (95% CI, 98.0 to 99.7), respectively. In patients whose plasma samples had a ctDNA fraction ≥ 1.0%, the PPA was 100.0% (15/15; 95% CI, 78.2 to 100.0). Three patients with MSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti–programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months. One patient with an aggressive cancer of an unknown primary site benefited from pembrolizumab after rapid detection of MSI-H by ctDNA genotyping. CONCLUSION: ctDNA genotyping was able to detect MSI with high concordance to validated tissue-based MSI testing, especially in patients with tumors that have sufficient ctDNA shedding. Furthermore, ctDNA genotyping enabled identification of patients with MSI-H tumors who benefited from immune checkpoint inhibitor treatment. [ABSTRACT FROM AUTHOR]

Chromosomal instability is one of the characteristics of gastric cancer (GC)[1],[2] associated with frequent amplifications of receptor tyrosine kinase (RTK)-related genes. We present a patient with I EGFR i -amplified GC who acquired substantial numbers of I EGFR i mutations and I MET i amplification during the cetuximab treatment as detected by serial ctDNA sequencing. The number of I EGFR i mutations (range, 1-7; Fig 3C) or known actionable I EGFR i mutations (range, 1-6; Fig 3D) were lower than those seen in our GC patient with 22 I EGFR i mutations, including seven known actionable mutations. [Extracted from the article]

PURPOSE: To understand the mutational landscape of circulating tumor DNA (ctDNA) and tumor tissue of patients with hormone receptor–positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) metastatic breast cancer (MBC) treated with abemaciclib + endocrine therapy (ET). METHODS: Blood samples for ctDNA and/or tissue samples were collected from abemaciclib-treated patients with HR+/HER2– MBC enrolled in the SCRUM-Japan MONSTAR-SCREEN project. Blood samples were collected before abemaciclib initiation (baseline) and at disease progression/abemaciclib discontinuation (post abemaciclib treatment). Clinical and genomic characteristics including neoplastic burden (measured by shedding rate and maximum variant allele frequency [VAF]) were assessed at baseline. Genomic alterations in ctDNA were compared in paired baseline and post abemaciclib treatment samples. RESULTS: All patients (N = 97) were female (median age, 57 years [IQR, 50-67]). In baseline ctDNA (n = 77), PIK3CA (37%), TP53 (28%), ESR1 (16%), and GATA3 (11%) were the most frequently mutated genes. Baseline tissue samples (n = 79) showed similar alteration frequencies. Among patients with baseline ctDNA data, 30% had received previous ET. ESR1 alteration frequency (35% v 8%; P <.01), median shedding rate (3 v 2), and maximum somatic VAF (4 v 0.8; both P <.05) were significantly higher in ctDNA from patients with previous ET than those without previous ET. In paired ctDNA samples (n = 33), PIK3CA and ESR1 alteration frequencies were higher after abemaciclib treatment than at baseline, though not statistically significant. Among the post-treatment alterations, those newly acquired were detected most frequently in FGF3/4/19 (18%); PIK3CA , TP53 , CCND1 , and RB1 (all 15%); and ESR1 (12%). CONCLUSION: We summarized the ctDNA and cancer tissue mutational landscape, including overall neoplastic burden and PIK3CA and ESR1 hotspot mutations in abemaciclib-treated patients with HR+/HER2– MBC. The data provide insights that could help optimize treatment strategies in this population. [ABSTRACT FROM AUTHOR]

PURPOSE: Earlier detection of cancer recurrence using circulating tumor DNA (ctDNA) to detect molecular residual disease (MRD) has the potential to dramatically affect cancer management. We review evidence supporting the use of ctDNA as a biomarker for detection of MRD and highlight the potential impact that ctDNA testing could have on the conduct of clinical trials. METHODS: We searched the literature using MEDLINE (via PubMed) for articles from January 1, 2000, focusing on studies that assessed ctDNA as a predictor of cancer recurrence. Broadly focused searches on ctDNA and cancer were also performed to provide additional background information. www.clinialtrials.gov was searched to identify trials that incorporate ctDNA testing. RESULTS: Numerous studies across different cancer types indicate that ctDNA-based MRD detection predicts recurrence with high sensitivity and specificity, and with lead times that precede standard imaging by up to 12 months. Recently, ctDNA testing has started being used to enroll MRD-positive patients at high risk of recurrence into trials, promising gains in statistical power that allow clinical utility to be demonstrated with smaller cohorts. Trials where ctDNA testing based-MRD detection is used to stratify patients into low or high-risk categories for treatment assignment are also ongoing. In addition, there is increasing evidence supporting the use of ctDNA dynamics or clearance as a surrogate end point, which could significantly reduce trial duration. CONCLUSION: ctDNA-based trial enrichment across many cancers seems likely to become increasingly common for cost- and time-reduction benefits. Trial efficiency could also benefit from using ctDNA as a surrogate end point, leading to accelerated approval of new therapeutics. A clear demonstration of efficacy from trials that use ctDNA-based MRD detection to assign treatment could transform clinical practice. [ABSTRACT FROM AUTHOR]

PURPOSE: Earlier detection of cancer recurrence using circulating tumor DNA (ctDNA) to detect molecular residual disease (MRD) has the potential to dramatically affect cancer management. We review evidence supporting the use of ctDNA as a biomarker for detection of MRD and highlight the potential impact that ctDNA testing could have on the conduct of clinical trials. METHODS: We searched the literature using MEDLINE (via PubMed) for articles from January 1, 2000, focusing on studies that assessed ctDNA as a predictor of cancer recurrence. Broadly focused searches on ctDNA and cancer were also performed to provide additional background information. www.clinialtrials.gov was searched to identify trials that incorporate ctDNA testing. RESULTS: Numerous studies across different cancer types indicate that ctDNA-based MRD detection predicts recurrence with high sensitivity and specificity, and with lead times that precede standard imaging by up to 12 months. Recently, ctDNA testing has started being used to enroll MRD-positive patients at high risk of recurrence into trials, promising gains in statistical power that allow clinical utility to be demonstrated with smaller cohorts. Trials where ctDNA testing based-MRD detection is used to stratify patients into low or high-risk categories for treatment assignment are also ongoing. In addition, there is increasing evidence supporting the use of ctDNA dynamics or clearance as a surrogate end point, which could significantly reduce trial duration. CONCLUSION: ctDNA-based trial enrichment across many cancers seems likely to become increasingly common for cost- and time-reduction benefits. Trial efficiency could also benefit from using ctDNA as a surrogate end point, leading to accelerated approval of new therapeutics. A clear demonstration of efficacy from trials that use ctDNA-based MRD detection to assign treatment could transform clinical practice. [ABSTRACT FROM AUTHOR]

PURPOSE: ERBB2 amplification (human epidermal growth factor receptor 2 positivity [HER2+]) in metastatic colorectal cancer (mCRC) has important therapeutic implications that necessitate the need for accurate diagnostics. The study purpose was to establish and validate harmonized diagnostic criteria for HER2+ mCRC among 3 groups (GI-SCREEN-Japan, NCTN-SWOG-USA, and Korea). PATIENTS AND METHODS: We assessed HER2 status by immunohistochemistry (IHC), ERBB2/CEP17 ratio, gene copy number (GCN) by fluorescence in situ hybridization (FISH), and copy number variation (CNV) using two targeted next-generation sequencing (NGS) panels. Tumor samples from 475 and 16 patients with mCRC in exploratory and validation cohorts, respectively, were used for cross-validation of the NGS panels. RESULTS: Consensus diagnostic criteria among the 3 groups for HER2+ mCRC were established as follows: IHC 3+ or IHC 2+ and ERBB2/CEP17 ratio by FISH ≥ 2.0, tumor content > 10% for surgically resected specimens, and necessary tumor content not defined for biopsy specimens. The median GCN and CNV for HER2+ patients were 10.9 and 27.7 compared with 2.5 (P <.0001) and 3.5 (P <.0001), respectively, in HER2-negative patients. These findings were validated in a validation cohort (GCN, 16.2 v 2.4 [ P =.0002]; CNV, 42.5 v 2.0 [ P =.0003]). GCN correlated with CNV in both cohorts (exploratory, r = 0.90; validation, r = 0.97; P <.0001). CNV in cross-validation of the 2 NGS panels also showed a strong correlation (r = 0.98; P <.0001). CNV in patients who fulfilled the consensus criteria was > 4.0 in all, which demonstrates the accuracy of the IHC/FISH criteria and cross-validation of NGS panels. CONCLUSION: We have established and verified harmonized diagnostic criteria for HER2+ and demonstrated consistency between IHC/FISH and CNV determined by NGS in mCRC. [ABSTRACT FROM AUTHOR]