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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: 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]

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: 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]